6-phenyltetrahydro-1,3-oxazin-2-one derivative and pharmaceutical composition containing the same

ABSTRACT

A 6-phenyltetrahydro-1,3-oxazin-2-one derivative having the formula (I):                    
     wherein, R 1  is an unsubstituted or substituted C 1  to C 8  alkyl group; an unsubstituted or substituted C 3  to C 7  cycloalkyl group;, etc., R 2  is a C 1  to C 4  alkyl group, R 3  is H; an unsubstituted or substituted C 1  to C 5  alkyl group; etc., R 4  is H; an unsubstituted or substituted C 1  to C 6  alkyl group, and R 5  and R 6  are independently a hydrogen atom; an unsubstituted or substituted C 1  to C 5  alkyl group; etc. an optical isomer thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvate thereof and pharmaceutical compositions containing the same, in particular a drug for the prevention or treatment of inflammatory diseases and a drug for asthma. 
     The above 6-phenyltetrahydro-1,3-oxazin-2-one derivative has a strong type IV PDE inhibitory activity and has a bronchiodilator and antiinflammatory effects.

TECHNICAL FIELD

The present invention relates to a novel6-phenyltetrahydro-1,3-oxazin-2-one derivative having a type IVphosphodiesterase (PDE) inhibitory activity and a pharmaceuticalcomposition containing the same.

BACKGROUND ART

Intracellular second messenger cAMP is involved in relaxation of airwaysmooth muscles and regulation of the functions of inflammatory cells.cAMP is broken down by phosphodiesterase (PDE) and becomes inactive5′-AMP. It is considered that an increase in intracellular concentrationof cAMP due to suppression of cAMP metabolism by PDE would givebronchodilating and anti-inflammatory actions and would exhibit atherapeutic effect on inflammatory diseases such as asthma [Eur. Respir.J., 7, 579 (1994)]. Up to now, PDE has been classified into fiveisozymes (i.e., types I to V PDE). Their distributions differ among onthe tissue [Trends Pharm., Sci., 12, 19 (1991)]. This suggests apossibility that selective inhibitors of PDE isozymes would result intissue specific increase of intracellular cAMP concentration.

It is reported that a selective inhibitor of type IV PDE isozymesuppresses inflammatory cells functions [Thorax, 46, 512 (1991)] and isuseful for inflammatory diseases such as asthma [J. Pharmacol. Exp.Ther., 266, 306 (1993)] and dermatitis [Br. J. Pharmacol., 112, 332(1994)] and autoimmune diseases such as multiple sclerosis [NatureMedicine, 1, 244 (1994)] and rheumatoid arthritis [Clin. Exp. Immunol.,100, 126 (1995)]. In addition, it is thought that cardiovascular sideeffect caused by non-selective PDE inhibitors such as theophylline couldbe reduced by using selective type IV PDE inhibitor. Rolipram having thefollowing formula (Japanese Unexamined Patent Publication (Kokai)JP-A-50-157360) is known as a compound having a specific inhibitoryactivity against type IV PDE.

Other compounds having a specific inhibitory activity against type IVPDE are known (JP-A-62-281864, U.S. Pat. No. 5128358, WO 94/10118, WO94/12461, JP-A-5-117239, JP-A-7-101861, WO 95/03794, WO 95/08534, etc.),but they have not been clinically applied up to now. Development of moreuseful compounds is desired. Further, JP-A-5-213893,discloses, as anantifungal agent, a compound having the following formula (II):

wherein, Ar represents an unsubstituted or substituted aryl group orheterocycle and n is 1 or 2. JP-A-6-1777 discloses, as an antifungalagent, a compound the following formula (III):

wherein, Ar represents an unsubstituted or substituted aryl group or aheterocyclic ring, n is 1 or 2, and Z is N or CH. JP-A-5-148248discloses a compound having the following formula (IV):

wherein, R₁ and R₂ may be the same or different and represents ahydrogen atom or an unsubstituted or substituted phenyl group, R₄ is anunsubstituted or substituted C₁ to C₁₀ alkyl group, R₅ represents a C₁to C₁₀ alkyl group, and n is 0 or 1, as a compound useful for theproduction of a carbapenem based antibiotic or carbacephem basedantibiotic. JP-A-7-17946 discloses a compound having formula (V):

wherein, R₁ to R₆ each independently represent hydrogen; a C₁ to C₄alkyl group; a hydroxy group; a C₁ to C₄ alkoxy group or a C₁ to C₄alkyl group substituted with a —SO₃H group; a phenyl group; a benzylgroup; a halogen atom; a phenyl group substituted with a C₁ to C₄ alkoxygroup or a —SO₃H group; a benzyl group; and n is 0 or 1, as a startingmaterial, when producing 2-(2′-aminoalkylmercapto)ethanol useful as asynthesis intermediate for a dye.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel compound havinga type IV phosphodiesterase (PDE) inhibitory activity and apharmaceutical composition containing the same.

In accordance with the present invention, there are provided a6-phenyltetrahydro-1,3-oxazin-2-one derivative having the formula (I):

wherein, R₁ represents an unsubstituted or substituted C₁ to C₈ alkylgroup; an unsubstituted or substituted C₃ to C₇ cycloalkyl group; anunsubstituted or substituted heterocycle; or a polycyclic hydrocarbon,R₂ represents a C₁ to C₄ alkyl group, R₃ is a hydrogen atom; anunsubstituted or substituted C₁ to C₅ alkyl group; an unsubstituted orsubstituted C₃ to C₇ cycloalkyl group; an unsubstituted or substitutedaryl group; an unsubstituted or substituted heteroaryl group whichcontains at least one hetero atom selected from the group consisting ofan oxygen atom, nitrogen atom, and sulfur atom; or acyl group, R₄ is ahydrogen atom; an unsubstituted or substituted C₁ to C₆ alkyl group; anunsubstituted or substituted aryl group; an unsubstituted or substitutedheteroaryl group which contains at least one hetero atom selected fromthe group consisting of an oxygen atom, a nitrogen atom, and a sulfuratom, and R₅ and R₆ are independently a hydrogen atom; an unsubstitutedor substituted C₁ to C₅ alkyl group; an unsubstituted or substituted C₃to C₇ cycloalkyl group; or an unsubstituted or substituted aryl groupwhich may contain at least one hetero atom selected from the groupconsisting of an oxygen atom, a nitrogen atom, and a sulfur atom anoptical isomer or a pharmacologically acceptable salt thereof, or ahydrate thereof or a solvate thereof.

In accordance with the present invention, there is provided apharmaceutical composition comprising, as an essential ingredient, theabove derivative, an optical isomer or a pharmacologically acceptablesalt thereof, or a hydrate thereof or a solvate thereof, specifically anagent for the prevention or treatment of inflammatory diseases or anantiasthmatic agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors conducted a search for a novel compound having atype IV PDE inhibitory activity and, as a result, found that the above6-phenyltetrahydro-1,3-oxazin-2-one derivative had a strong type IV PDEinhibitory activity and had a bronchodilator and antiinflammatoryeffects, whereby the present invention was completed.

The present invention will now be explained in detail.

As the C₁ to C₈ linear or branched alkyl group of R₁ of the compoundhaving the above formula (I), methyl, ethyl, propyl, isopropyl, n-butyl,2-methylpropyl, sec-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl,n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl,n-octyl group, etc. may be mentioned. These may be substituted with ahalogen atom; a hydroxy group; a nitro group; a cyano group; an aminogroup; a carboxyl group; an aryl group such as phenyl, tolyl or napthyl;a heteroaryl group such as pyridyl, thiazolyl, thienyl, furyl, orquinolyl; a cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; haloalkyl; carbamoyl; alkoxy; alkylcarbonyl,etc. As the substituted C₁ to C₈ alkyl group, for example,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-methylcyclopropylmethyl, 1-phenylcyclopropylmethyl,benzyl, phenethyl, 4-fluorophenethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl, 2-(1-naphthyl)ethyl, 2-(2-pyridyl)ethyl,2-(4-methyl-5-thiazolyl)ethyl, 2-(benzyloxy)ethyl,2-(phenethyloxy)ethyl, 2-(methoxy)ethyl, 3-(methoxy)propyl,4-(methoxy)butyl, 2-(ethoxy)ethyl, 3-(ethoxy)propyl, 2-(butoxy)ethyl,2-(cyclopropylmethyloxy)ethyl, 2-(cyclopentyloxy)ethyl,2-(4-methyl-1-piperazinyl)ethyl, 3-(4-benzyl-1-piperazinyl)propyl, etc.may be mentioned.

As the C₃ to C₇ cycloalkyl group of R₁, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc. may be mentioned. This may besubstituted with an alkyl group; a halogen atom; a hydroxy group; anitro group; a cyano group; an amino group; a carboxyl group; an arylgroup such as phenyl, tolyl or napthyl; a heteroaryl group such aspyridyl, thiazolyl, thienyl, furyl, or quinolyl; a cycloalkyl group suchas cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; a haloalkylgroup; a carbamoyl group; an alkoxy group; an alkylcarbonyl group, etc.As the substituted C₃ to C₇ cycloalkyl group, for example,4-phenylcyclohexyl, 1-methylcyclopentyl, or 3-methylcyclopentyl may bementioned.

As the heterocyclic ring of R₁, a pyridyl group; a thiazolyl, furyl,thienyl, tetrahydrofuryl, piperidyl, etc. may be mentioned. These may besubstituted with an alkyl group; a halogen atom; a hydroxy group; anitro group; a cyano group; an amino group; a carboxyl group; an arylgroup such as phenyl, tolyl or napthyl; a heteroaryl group such aspyridyl, thiazolyl, thienyl, furyl, or quinolyl an aralkyl group such asbenzyl, phenethyl, 1-naphthylmethyl, or 4-pyridylmethyl; a cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; ahaloalkyl; a carbamoyl; an alkoxy group; an alkylcarbonyl group, etc. Asthe substituted heterocycle, for example, 1-benzyl-4-piperidyl,2-nitropyridyl, or 3-tetrahydrofuryl may be mentioned.

As the polycyclic hydrocarbon of R₁, a dibenzocycloheptyl or indanyl maybe mentioned.

As R₁, preferably a C₁ to C₆ alkyl group; a C₁ to C₅ alkyl groupsubstituted with a group selected from the group consisting of anunsubstituted or substituted aryl group an unsubstituted or substitutedheteroaryl group which contains at least one hetero atom selected fromthe group consisting of oxygen atom, a nitrogen atom, and a sulfur atom,an unsubstituted or substituted heterocyclic ring, an unsubstituted orsubstituted alkoxy group, and an unsubstituted or substituted C₃ to C₆cycloalkyl group; a cyclopentyl group; a benzylpiperidyl group; atetrahydrofuryl group; a dibenzocycloheptyl group or an indanyl groupmay be mentioned. More preferably, methyl; butyl; 2-methylpropyl;2-ethylbutyl; a C₁ to C₅ alkyl group substituted with phenyl, pyridyl,naphthyl, methylthiazolyl, fluorophenyl, benzylpiperazinyl,benzylpiperidyl, benzyloxy, cyclopropylmethoxy, or a C₃ to C₆ cycloalkylgroup, which may have a phenyl group; a cyclopentyl group; acyclopropylmethyl group; a benzylpiperidyl group; a tetrahydrofurylgroup; a dibenzocycloheptyl group or a 2-indanyl group may be mentioned.

As the C₁ to C₄ linear or branched alkyl group of R₂, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc. may be mentioned.Preferably methyl or ethyl may be mentioned. More preferably, methyl maybe mentioned.

As R₃, a hydrogen atom may be mentioned. Further, as the C₁ to C₅ linearor branched alkyl group of R₃, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, t-butyl, n-pentyl, etc. may be mentioned. The C₁ toC₅ linear or branched alkyl group may be substituted with an aryl group(e.g. phenyl, tolyl, naphtyl, etc.) which may be substituted with ahalogen atom, an unsubstituted or substituted heteroaryl groups, whichcontains at least one hetero atom selected from the group consisting ofan oxygen atom, a nitrogen atom, and a sulfur atom (e.g. pyridyl,thiazolyl, furyl, thienyl, quinolyl, etc.), or with an alkoxycarbonylgroup. As the substituted C₁ to C₅ alkyl group, for example,ethoxycarbonylmethyl, benzyl, 4-bromobenzyl, phenethyl, 3-phenylpropyl,pyridylmethyl, 4-phenylbutyl, 5-phenylpentyl, furylmethyl,thiazolylmethyl, 2-quinolylmethyl, 1-naphthylmethyl, etc. may mentioned.

As the C₃ to C₇ cycloalkyl group of R₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc. may be mentioned.

As the aryl group of R₃, phenyl, tolyl, napthyl, etc. may be mentioned.

As the heteroaryl group which contains at least one hetero atom selectedfrom the group consisting of oxygen, nitrogen and sulfur of R₃, pyridyl,thiazolyl, furyl, thienyl, etc. may be mentioned.

As the acyl group of R₃, formyl, acetyl, propionyl, benzoyl,2-naphthoyl, 3-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl, etc. may bementioned.

As R₃, preferably a hydrogen; a C₁ to C₄ alkyl group; an aryl group; anunsubstituted or substituted heteroaryl group which may be substitutedwith halogen and may contain at least one hetero atom selected from thegroup consisting of oxygen, nitrogen, and sulfur, a C₁ to C₃ alkyl groupsubstituted with a C₄ to C₆ cycloalkyl group containing at least onehetero atom selected from the group consisting of oxygen, nitrogen, andsulfur; ethoxycarbonylmethyl; or benzoyl may be mentioned. Morepreferably, hydrogen, methyl, ethyl, benzyl, 2-pyridylmethyl, or4-pyridylmethyl may be mentioned.

As R₄, a hydrogen atom may be mentioned. As the C₁ to C₆ linear orbranched alkyl group, methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, t-butyl, pentyl, hexyl, etc. may be mentioned. These may besubstituted with any substituent group. As the aryl group of R₄, phenyl,tolyl, napthyl, 4-methylphenyl, 4-chlorophenyl, etc. may be mentioned.

As the heteroaryl group which contains at least one hetero atom selectedfrom the group consisting of oxygen, nitrogen and sulfur of R₄, pyridyl,thiazolyl, furyl, thienyl, etc. may be mentioned. These may besubstituted with any substituent group.

As R₄, preferably hydrogen, methyl, ethyl, phenyl, or pyridyl may bementioned. More preferably hydrogen or methyl may be mentioned.

R₅ and R₆ may independently be hydrogen. Further, R₅ and R₆ mayindependently be a C₁ to C₆ linear or branched alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl,hexyl, etc. These C₁ to C₆ linear or branched alkyl groups may besubstituted with a halogen atom; a hydroxy group; a cyano group; anamino group; a carboxyl group; a cycloalkyl group; a haloalkyl group; acarbamoyl group; an alkoxy group; an alkylcarbonyl group; or an arylgroup or an unsubstituted or substituted heteroaryl group, which maycontain at least one hetero atom selected from the group consisting ofoxygen, nitrogen, and sulfur.

R₅ and R₆ may independently be an aryl group such as phenyl, tolyl,napthyl, 4-methylphenyl, 4-chlorophenyl, etc.; or a heteroaryl groupwhich contains at least one hetero atom selected from the groupconsisting of oxygen, nitrogen and sulfur, such as pyridyl, thiazolyl,furyl, thienyl, etc. may be mentioned. These groups may be substitutedwith a halogen atom, a hydroxy group, a cyano group, an amino group, acarboxyl group, an alkyl group, a cycloalkyl group, a haloalkyl group, acarbamoyl group, an alkoxy group, or an alkylcarbonyl group.

As R₅ and R₆, preferably hydrogen, methyl, or phenyl, may be mentioned.More preferably, hydrogen or methyl may be mentioned.

Specific compounds having the above formula (I) are those produced bythe Examples mentioned below.

The compounds having the above formula (I) have asymmetric carbon atomsand include optical isomers. The optical isomers are also within thescope of the present invention. Further, the salts of the compoundshaving the above formula (I) and their optical isomers are also withinthe scope of the present invention. As their salts, pharmacologicallyacceptable salts are preferable. As the pharmacologically acceptablesalts, for example, inorganic acid salts such as hydrochlorides,hydrobromides hydroiodides, and phosphates, etc. and organic acid saltssuch as oxalates, maleates, fumarates, lactates, malates, citrates,tartarates, benzoates, methanesulfonates, and p-toluenesulfonates, etc.may be mentioned.

Further, the present invention includes hydrates and solvates of thecompounds having the above formula (I), their optical isomers, and theirsalts. As the solvent of the solvates, methanol, ethanol, isopropanol,butanol, acetone, ethyl acetate, chloroform, etc. may be mentioned.

The compounds having the above formula (I) may be produced by thefollowing method combining known reactions. An example of the productionprocess will be explained by the following reaction schemes.

The compounds (XI) and (XIII) in the above reaction scheme correspond tocompounds having the above formula (I).

Step (1): A ketone derivative (or an aldehyde derivative when R₄represented a hydrogen atom) (VI) was reacted with a nitrile (R₅R₆CHCN)in the presence of a base such as lithium diisopropylamide (LDA) tosynthesize a nitrile derivative (VII). In general, as the reactionsolvent, an ether solvent such as diethyl ether or tetrahydrofuran isused and the reaction temperature is 0° C. or less.

Step (2): The nitrile derivative (VII) is converted to an aminoalcoholderivative (VIII) by a reducing agent such as lithium aluminum hydride.

Step (3): The aminoalcohol derivative (VIII) is reacted with ahalogenated formic acid ester having the formula (IX), wherein X is ahalogen atom and R is an alkyl group in the presence of a base such astriethylamine or pyridine to synthesize the compound (X).

Step (4): The compound (X) is intramolecularly condensed with a basesuch as sodium hydride or sodium methoxide to obtain a ring-closedcompound (XI).

Step (5): The compound (XI) is reacted with an alkyl halide (XII),wherein X is a halogen atom, in the presence of a base such as sodiumhydride to obtain the compound (XIII).

The compounds obtained in the above steps are isolated by known methods(e.g., crystallization, recrystallization, chromatography, etc.), butsometimes the synthesis intermediates are used for the next stepswithout further purification.

The starting materials, which may be used in the above reaction process,are commercially available products or may be synthesized from knowncompounds. For example, the ketone derivative (U/C) may be produced by aknown method (for example, see WO94/10118).

When the compound of the present invention is used as a therapeuticagent, it can be administered alone or together with a pharmacologicallyacceptable carrier. The composition is determined by the solubility ofthe compound, its chemical properties, the delivery route, medicationplan, etc.

For instance, it can be orally administered in the form of granules,powders, tablets, pills, hard gelatin capsules, soft gelatin capsules,syrups, emulsions, suspensions, liquids, etc. or can be administered bya non-oral route such as an injection (intravenous, intramuscular, orhypodermic), ointment, suppository, aerosol, etc. Alternatively, it maybe made a powder for injection which is prepared at the time of use.Organic or inorganic solid or liquid carriers or diluents which aresuitable for oral, rectal, non-oral, and topical administration can beused together with the compound of the invention. For example, in thecase of oral administration, the compound can be prepared in the desiredform by using excipients such as lactose, D-glucose, corn starch, andsucrose, disintegrants such as calcium carboxymethylcellulose,hydroxypropylcellulose, etc., lubricants such as calcium stearate,magnesium stearate, talc, polyethylene glycol, and hydrogenated oil,humectants such as hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinyl alcohol, gelatin, and gum arabic, anda surfactant and flavoring agents if necessary.

When administered by a non-oral route, it is possible to use a diluentsuch as water, ethanol, glycerine, propylene glycol, polyethyleneglycol, agar, and tragacanth and, if necessary, use a solution adjuvant,buffering agent, preservative, flavoring agent, and colorant, etc.Pharmaceutical compositions may be prepared by general methods.

The clinical dosage generally ranges 0.01 to 1000 mg in terms of thecompound of the invention per adult per day when orally administered,preferably 0.01 to 100 mg, but can be appropriately arranged dependingupon the age, condition, symptoms, other drugs administered at the sametime, etc. The daily dosage of the drug (compound of present invention)can be administered once a day or twice or three times a day withsuitable intervals or intermittently. When administered by injection,one dosage in an amount of 0.001 to 100 mg per adult with or withoutintervals is preferable.

EXAMPLES

The present example will be explained in detail below by Examples andTest Examples, but of course the present invention is not limited tothese Examples and Test Examples.

Example 1 Synthesis of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (CompoundNo. 1 of Table 1) (1) Synthesis of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile

A solution of diisopropylamine (0.67 g, 6.62 mM) in driedtetrahydrofuran (5 ml) was cooled to −78° C. A hexane solution ofn-butyllithium (6.62 mM) was dropped into this solution, then this wasstirred at that temperature for 30 minutes. Next, acetonitrile (0.27 g,6.62 mM) was dropped into this solution and the result stirred for afurther 30 minutes, then a solution of 3,4-dimethoxybenzaldehyde (1.00g, 6.02 mM) in dried tetrahydrofuran (5 ml) was added and the mixturestirred at that temperature for 4 hours. An aqueous ammonium chloridewas poured into the obtained solution, which was warmed to roomtemperature and extracted with diethyl ether. The organic layer wasdried over anhydrous magnesium sulfate, then the solvent was removed invacuo to obtain a crude product (1.25 g) of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile as a yellow oil. Thecrude product thus obtained had sufficient purity without purification,therefore could be used for the next reaction as it was.

¹H-NMR (400 MHz, CDCl₃) δ2.74 (1H, dd, J=16.60, 5.86 Hz), 2.79 (1H, dd,J=16.60, 5.86 Hz), 3.89 (3H, s), 3.91 (3H, s), 5.00 (1H, t, J=5.86 Hz),6.87 (1H, d, J=8.30 Hz), 6.93 (1H, dd, J=8.30, 1.95 Hz), 6.96 (1H, d,J=1.95 Hz)

(2) Synthesis of 3-amino-1-(3,4-dimethoxyphenyl)-1-propanol

A solution of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile (1.25 g,6.02 mM) in dried tetrahydrofuran (25 ml) was dropped into a solution oflithium aluminum hydride (0.55 g, 14.48 mM) in dried tetrahydrofuran (40ml) at 0° C. This was gradually warmed to room temperature and stirredfor 1 hour. Next, the reaction solution was again cooled to 0° C., waterwas carefully added to it, then the mixture was stirred at roomtemperature for 30 minutes. Next, the solution was filtered throughCelite, the filtrate was dried over anhydrous sodium sulfate, then thesolvent was removed in vacuo to obtain a crude product of3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g). The crude productobtained here had a sufficient purity even without purification, socould be used as it was for the next reaction.

¹H-NMR (400 MHz, CDCl₃) δ1.72-1.87 (2H, m), 2.95 (1H, ddd, J=12.70,9.28, 3.91 Hz), 3.11 (1H, ddd, J=12.70, 5.37, 5.37 Hz), 3.87 (3H, s),3.90 (3H, s), 4.90 (1H, dd, J=7.30, 2.93 Hz), 6.83 (1H, d, J=8.30 Hz),6.88 (1H, dd, J=8.30, 1.96 Hz), 6.97 (1H, d, J=1.96 Hz)

(3) Synthesis of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g, 6.02 mM),triethylamine (0.84 g, 8.30 mM), and methyl chloroformate (0.59 g, 6.25mM) were dissolved in dried tetrahydrofuran (80 ml) and stirred at roomtemperature for 5.5 hours. The solution obtained was poured into icewater and extracted with methylene chloride. The organic layer was driedover anhydrous sodium sulfate, then the solvent was removed in vacuo toobtain a crude product of1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol as a yellowoil. Next, the crude product was dissolved in dried benzene (5 ml). Themixture was dropped into a solution of sodium hydride (60%) (0.24 g,6.04 mM) in dried benzene (40 ml) at room temperature, water was addedinto the reaction solution and the mixture stirred at that temperaturefor 24 hours, which was then extracted with methylene chloride. Theextract was dried over anhydrous sodium sulfate, then the solvent wasremoved in vacuo to obtain a crude product as a brown solid. The crudeproduct was washed with ether to obtain the above-described compound0.86 g (yield 63.1%) as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ2.07-2.18 (1H, m), 2.19-2.23 (1H, m), 3.38-3.44(1H, m), 3.50 (1H, ddd, J=10.74, 10.74, 4.88 Hz), 3.89 (3H, s), 3.90(3H, s), 5.27 (1H, m), 6.86 (1H, d, J=8.30 Hz), 6.90 (1H, dd, J=8.30,1.46 Hz), 6.92 (1H, d, J=1.46 Hz)

Example 2 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 2 of Table 1) (1) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile wasobtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.67 (2H, m), 1.79-1.98 (6H, m), 2.74-2.76(2H, m), 3.84 (3H, s), 4.80 (1H, m), 4.97 (1H, t, J=5.86 Hz), 6.85 (1H,d, J=8.30 Hz), 6.90 (1H, dd, J=8.30, 1.95 Hz), 6.95 (1H, d, J=1.95 Hz)

(2) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 60.5%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.57-1.66 (2H, m), 1.79-1.97 (6H, m), 2.03-2.21(2H, m), 3.36-3.42 (1H, m), 3.47 (1H, ddd, J=10.75, 10.75, 4.88 Hz),3.85 (3H, s), 4.80 (1H, m), 5.26 (1H, dd, J=9.77, 2.45 Hz), 5.81 (1H,broad s), 6.85 (1H, d, J=8.30 Hz), 6.87-6.90 (2H, m)

Example 3 Synthesis of6-(3-butoxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-13-oxazin-2-one(Compound No. 3 of Table 1) (1) Synthesis of3-butoxy-4-methoxybenzaldehyde

Isovanillin (6.00 g, 39.4 mM), butyl iodide (5.7 ml, 49.3 mM), andanhydrous potassium carbonate (6.8 g, 49.3 mM) were dissolved in drieddimethylformamide (50 ml) and stirred at room temperature for one night,then the solution was diluted with ethyl acetate (300 ml) and washedwith water. The organic layer was dried over anhydrous magnesium sulfateand the solvent was removed in vacuo to obtain a residue as a lightyellow oil. The residue was purified by flash chromatography (SiO₂:eluted by 20% ethyl acetate/hexane solution). The solvent was removed invacuo and the resultant product was dried to obtain3-butoxy-4-methoxy-3-benzaldehyde 8.09 g (yield 99.0%) as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ0.99 (3H, t, J=7.32 Hz), 1.46-1.55 (2H, m),1.82-1.89 (2H, m), 3.95 (3H, s), 4.08 (2H, t, J=6.83 Hz), 6.98 (1H, d,J=7.81 Hz), 7.40-7.46 (2H, m), 9.84 (1H, s)

(2) Synthesis of 3-(3-butoxy-4-methoxyphenyl)-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-butoxy-4-methoxybenzaldehyde instead of 3,4-dimethoxybenzaldehyde,3-(3-butoxy-4-methoxyphenyl)-3-hydroxypropiononitrile was obtained as alight yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.98 (3H, t, J=7.32 Hz), 1.49 (2H, m, J=7.32Hz), 1.83 (2H, m), 2.72 (1H, dd, J=16.60, 6.35 Hz), 2.77 (1H, dd,J=16.60, 6.35 Hz), 3.86 (3H, s), 4.02 (2H, t, J=6.84 Hz), 4.97 (1H, t,J=6.35 Hz), 6.85 (1H, d, J=8.30 Hz), 6.90 (1H, dd, J=8.30, 1.95 Hz),6.94 (1H, d, J=1.95 Hz)

(3) Synthesis of6-(3-butoxy-4-methoxyphenyl)-3,4,5,6tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-butoxy-4-methoxyphenyl)-3-hydroxypropiononitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 61.1%) was obtained as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ0.98 (3H, t, J=7.33 Hz), 1.50 (2H, m, J=7.33Hz), 1.83 (2H, q, J=7.33 Hz), 2.07-2.22 (2H, m), 3.38-3.51 (2H, m), 3.87(3H, s), 4.03 (2H, t, J=7.33 Hz), 5.27 (1H, dd, J=9.76, 1.95 Hz), 5.47(1H, broad s), 6.84-6.92 (3H, m)

Example 4 Synthesis of 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3,4,56-tetrahydro-2H-1 3-oxazin-2-one (Compound No. 4 of Table 1) (1)Synthesis of 3-cyclopropylmethyloxy-4-methoxybenzaldehyde

Isovanillin (2.00 g, 13.14 mM), cyclopropylcarbinol (0.95 g, 13.14 mM),and triphenylphosphine (4.14 g, 15.77 mM) were dissolved in driedtetrahydrofuran (50 ml). Diethyl azodicarboxylate (2.75 g, 15.77 mM) wascarefully dropped into this solution at room temperature. The solutionwas stirred at room temperature for one night, then this solution wasdiluted with diethyl ether (100 ml) and was successively washed with aaqueous sodium hydroxide and water. The organic solution was dried overanhydrous magnesium sulfate and the solvent was removed in vacuo toobtain a residue as a light yellow oil. The residue was purified byflash chromatography (SiO₂: eluted by 25% hexane/ethyl acetate). Thesolvent was removed in vacuo and the resultant product was dried toobtain 3-cyclopropylmethyloxy-4-methoxybenzaldehyde 2.10 g (yield 77.4%)as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ0.36-0.40 (2H, m), 0.65-0.70 (2H, m), 1.34-1.38(1H, m), 3.92 (2H, d, J=6.84 Hz), 3.97 (3H, s), 6.98 (1H, d, J=8.30 Hz),7.39 (1H, d, J=1.95 Hz), 7.45 (1H, dd, J=8.30, 1.95 Hz), 9.84 (1H, s)

(2) Synthesis of3-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-cyclopropylmethyloxy-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile wasobtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.34-0.38 (2H, m), 0.63-0.68 (2H, m), 1.28-1.38(1H, m), 2.73 (1H, dd, J=16.60, 6.35 Hz), 2.77 (1H, dd, J=16.60, 6.35Hz), 3.86 (2H, d, J=7.81 Hz), 3.88 (3H, s), 4.97 (1H, t, J=6.35 Hz),6.87 (1H, d, J=8.30 Hz), 6.92 (1H, dd, J=8.30, 1.95 Hz), 6.94 (1H, d,J=1.95 Hz)

(3) Synthesis of 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3,45,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 60.5%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.34-0.38 (2H, m), 0.62-0.67 (2H, m), 1.29-1.39(1H, m), 2.03-2.20 (2H, m), 3.37-3.43 (1H, m), 3.48 (1H, ddd, J=11.23,11.23, 4.88 Hz), 3.86 (2H, d, J=7.32 Hz), 3.88 (3H, s), 5.26 (1H, dd,J=10.25, 2.93 Hz), 5.54 (1H, broad s), 6.85-6.91 (3H, m)

Example 5 Synthesis of6-(3,4-dimethoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 5 of Table 1) (1) Synthesis of3-(3,4-dimethoxyphenyl)-3-hydroxybutyronitrile

According to the same procedure as in Example 1(1), using3,4-dimethoxyacetophenone instead of 3,4-dimethoxybenzaldehyde,3-(3,4-dimethoxyphenyl)-3-hydroxybutyronitrile was obtained as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.77 (3H, s), 2.78 (1H, d, J=16.60 Hz), 2.84(1H, d, J=16.60 Hz), 3.89 (3H, s), 3.91 (3H, s), 6.86 (1H, d, J=8.30Hz), 6.97 (1H, dd, J=8.30, 1.95 Hz), 7.08 (1H, d, J=1.95 Hz)

(2) Synthesis of6-(3.4-dimethoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3,4-dimethoxyphenyl)-3-hydroxybutyronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 44.4%) was obtained as a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.67 (3H, s), 2.10-2.17 (1H, m), 2.31 (1H, ddd,J=14.16, 4.39, 4.39 Hz), 3.03-3.09 (1H, m), 3.25-3.31 (1H, m), 3.88 (3H,s), 3.89 (3H, s), 5.81 (1H, broad s), 6.86-6.92 (3H, m)

Example 6 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-methyl-3,4,56-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 6 of Table 1) (1)Synthesis of 3-cyclopentyloxy-4-methoxyacetophenone

A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM)in dried tetrahydrofuran (100 ml) was cooled to 0° C., a tetrahydrofuransolution of methyl magnesium bromide (136.20 mM) was dropped into thissolution, and the resultant mixture was stirred at that temperature for2 hours. A aqueous ammonium chloride was added to the solution obtained,which was then warmed to room temperature and extracted with ethylacetate. The extract was successively washed with brine and water. Theorganic solution was dried over anhydrous magnesium sulfate and thesolvent was removed in vacuo to obtain crude product of1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol 10.67 g as a light yellowoil. The crude product thus obtained of1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol (10.67 g) was dissolved indried methylene chloride (200 ml). Manganese dioxide (39.2 g) was addedto this solution. The resultant product was stirred vigorously at roomtemperature for 16 hours. The undissolved material in the solution wasremoved by filtration through Celite, then the filtrate was concentratedin vacuo to obtain residue as a yellow oil. The residue was purified byflash chromatography (SiO₂: eluted by 25% ethyl acetate/hexane). Thesolvent was removed in vacuo and the resultant product was dried toobtain 3-cyclopentyloxy-4-methoxyacetophenone 10.00 g (yield 94.4%) as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.61-1.64 (2H, m), 1.81-1.90 (4H, m), 1.97-2.00(2H, m), 2.56 (3H, s), 3.91 (3H, s), 4.86 (1H, m), 6.87 (1H, d, J=8.30Hz), 7.52 (1H, d, J=1.95 Hz), 7.55 (1H, dd, J=8.30, 1.95 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxyacetophenone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile was obtainedas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.59-1.62 (2H, m), 1.72 (3H, s), 1.80-1.94 (6H,m), 2.74 (1H, d, J=16.60 Hz), 2.80 (1H, d, J=16.60 Hz), 3.82 (3H, s),4.79 (1H, m), 6.83 (1H, d, J=8.30 Hz), 6.94 (1H, dd, J=8.30, 1.95 Hz),7.05 (1H, d, J=1.95 Hz)

(3) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 51.9%) was obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.69 (2H, m), 1.65 (3H, s), 1.78-1.97 (6H,m), 2.11 (1H, ddd, J=13.67, 10.74, 5.37 Hz), 2.28 (1H, ddd, J=13.67,3.90, 3.90 Hz), 3.03 (1H, ddd, J=11.23, 10.74, 3.90 Hz), 3.22-3.27 (1H,m), 3.84 (3H, s), 4.80 (1H, m), 5.80 (1H, broad s), 6.84 (2H, s), 6.90(1H, s)

Example 7 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 7 of Table 1) (1) Synthesis of3-cyclopentyloxy-4-methoxybenzophenone

A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM)in dried tetrahydrofuran (50 ml) was cooled to −78° C. A toluenesolution of phenyllithium (49.94 mM) was dropped into this solution andthe resultant mixture was stirred at that temperature for 5 hours. Waterwas added to the solution obtained, which was then warmed to roomtemperature and extracted with diethyl ether. The extract was dried overanhydrous magnesium sulfate, then the solvent was removed in vacuo toobtain a crude product ofα-(3-cyclopentyloxy-4-methoxyphenyl)benzylalcohol (13.56 g) as a yellowoil. The crude product (10.00 g) ofα-(3-cyclopentyloxy-4-methoxyphenyl)benzylalcohol was dissolved in driedmethylene chloride (110 ml) thus obtained, manganese dioxide (16.00 g)was added to the solution, then the solution was vigorously stirred atroom temperature for 2 days. The undissolved material in the solutionwas removed by filtration through Celite and the filtrate wasconcentrated in vacuo to obtain a residue as a yellow solid. The residuewas purified by flash chromatography (SiO₂: eluted by 20% ethylacetate/hexane). The solvent was removed in vacuo and the resultantproduct was dried to obtain 3-cyclopentyloxy-4-methoxybenzophenone 9.20g (yield 92.6%) as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.60-1.65 (2H, m), 1.82-2.00 (6H, m), 3.93 (3H,s), 4.84 (1H, m), 6.89 (1H, d, J=8.30 Hz), 7.38 (1H, dd, J=8.30, 1.95Hz), 7.46 (1H, d, J=1.95 Hz), 7.49 (2H, d, J=7.81 Hz), 7.55-7.59 (1H,m), 7.75-7.77 (2H, m)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-phenylpropiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxybenzophenone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-phenylpropiononitrilewas obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.54-1.62 (2H, m), 1.75-1.91 (6H, m), 2.80 (1H,broad s), 3.22 (1H, d, J=16.60 Hz), 3.26 (1H, d, J=16.60 Hz), 3.83 (3H,s), 4.69 (1H, m), 6.82 (1H, d, J=8.30 Hz), 6.88 (1H, dd, J=8.30, 2.44Hz), 6.91 (1H, d, J=2.44 Hz), 7.29-7.41 (5H, m)

(3) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-phenylpropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 48.6%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.59 (2H, m), 1.79-1.88 (6H, m), 2.61-2.65(2H, m), 3.23-3.29 (2H, m), 3.82 (3H, s), 4.73 (1H, m), 5.37 (1H, broads), 6.82 (1H, d, J=8.30 Hz), 6.91 (1H, dd, J=8.30, 2.44 Hz), 6.94 (1H,d, J=2.44 Hz), 7.28 (1H, d, J=7.33 Hz), 7.35 (2H, t, J=7.33 Hz), 7.41(2H, d, J=7.33 Hz)

Example 8 Synthesis of6-(3,4-dimethoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 8 of Table 1)

To a solution of the6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (1.20 g,5.06 mM) produced in Example 1 in dried N,N-dimethylformamide (30 ml)were added sodium hydride (60%) (0.41 g, 10.12 mM) and methyl iodide(1.44 g, 10.12 mM). The solution was then stirred at room temperaturefor one night. The reaction solution was carefully poured into icewater, then extracted with methylene chloride. The extract was driedover anhydrous sodium sulfate and the solvent was removed in vacuo toobtain a residue as a brown oil. The residue was purified by flashchromatography (SiO₂; eluted by 0.5% methanol/chloroform) to obtain theabove-described compound 0.28 g (yield 22.3%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ2.16-2.22 (2H, m), 3.05 (3H, s), 3.25-3.30 (1H,m), 3.49 (1H, ddd, J=11.72, 11.72, 5.86 Hz), 3.89 (3H, s), 3.90 (3H, s),5.23 (1H, dd, J=9.77, 3.42 Hz), 6.84-6.92 (3H, m)

Example 9 Synthesis of 3-benzyl-6-(34-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound No.9 of Table 1)

According to the same procedure as in Example 8, using benzyl bromideinstead of methyl iodide, the above-described compound (yield 74.1%) wasobtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.10-2.22 (2H, m), 3.21 (1H, ddd, J=11.72,5.86, 3.42 Hz), 3.32-3.39 (1H, m), 3.88 (3H, s), 3.89 (3H, s), 4.57 (1H,d, J=15.13 Hz), 4.68 (1H, d, J=15.13 Hz), 5.25 (1H, dd, J=9.77, 2.93Hz), 6.84 (1H, d, J=8.30 Hz), 6.88 (1H, dd, J=8.30, 1.95 Hz), 6.92 (1H,d, J=1.95 Hz), 7.28-7.38 (5H, m)

Example 10 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-13-oxazin-2-one (Compound No. 10 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 2 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 77.6%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.57-1.65 (2H, m), 1.79-1.96 (6H, m), 2.13-2.24(2H, m), 3.03 (3H, s), 3.25 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3.47 (1H,ddd, J=11.72, 10.25, 5.86 Hz), 3.84 (3H, s), 4.79 (1H, m), 5.21 (1H, dd,J=9.77, 3.42 Hz), 6.83-6.90 (3H, m)

Example 11 Synthesis of3-(4-bromobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 11 of Table 1)

According to the same procedure as in Example 10, using 4-bromobenzylbromide instead of methyl iodide, the above-described compound (yield99.5%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.66 (2H, m), 1.76-1.97 (6H, m), 2.07-2.23(2H, m), 3.18 (1H, ddd, J=11.23, 5.86, 3.91 Hz), 3.33 (1H, m), 3.84 (3H,s), 4.49 (1H, d, J=15.14 Hz), 4.60 (1H, d, J=15.14 Hz), 4.78 (1H, m),5.23 (1H, dd, J=9.76, 2.93 Hz), 6.82-6.88 (3H, m), 7.21 (2H, d, J=8.30Hz), 7.47 (2H, d, J=8.30 Hz)

Example 12 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-quinolylmethyl)-3,4,56-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 12 of Table 1)

To a solution of the6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(0.50 g, 1.72 mM) produced in Example 2 in dried N,N-dimethylformamide(23 ml) were added sodium hydride (60%) (0.15 g, 3.78 mM) and2-chloromethylquinoline hydrochloride (0.37 g, 1.72 mM). The solutionwas stirred at room temperature for one night. The reaction solution wascarefully poured into ice water, then was extracted with methylenechloride. The extract was dried over anhydrous sodium sulfate, and thesolvent was removed in vacuo. The residue obtained was purified by flashchromatography (SiO₂; eluted by 60% ethyl acetate/hexane) to obtainabove-described compound 0.63 g (yield 84.9%) as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.61 (2H, m), 1.78-1.95 (6H, m), 2.13-2.25(2H, m), 3.39-3.44 (1H, m), 3.50-3.57 (1H, m), 3.84 (3H, s), 4.78 (1H,m), 4.83 (1H, d, J=15.63 Hz), 4.96 (1H, d, J=15.63 Hz), 5.30 (1H, dd,J=9.28, 2.93 Hz), 6.84 (1H, d, J=8.30 Hz), 6.89-6.92 (2H, m), 7.52-7.56(2H, m), 7.72 (1H, t, J=7.81 Hz), 7.81 (1H, d, J=7.81 Hz), 8.05 (1H, d,J=8.30 Hz), 8.16 (1H, d, J=8.30 Hz)

Example 13 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1-naphthylmethyl)-3,4,5,6-tetrahydro-2H-13-oxazin-2-one (Compound No. 13 of Table 1)

According to the same procedure as in Example 10, using1-chloromethylnaphthalene instead of methyl iodide, the above-describedcompound (yield 36.2%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.60 (2H, m), 1.80-1.93 (6H, m), 2.07-2.13(2H, m), 3.13-3.17 (2H, m), 3.83 (3H, s), 4.76 (1H, m), 5.00 (1H, d,J=15.13 Hz), 5.17 (1H, dd, J=8.30, 3.90 Hz), 5.25 (1H, d, J=15.13 Hz),6.80 (1H, d, J=7.81 Hz), 6.83 (1H, dd, J=7.81, 1.46 Hz), 6.87 (1H, d,J=1.46 Hz), 7.39-7.60 (4H, m), 7.83 (1H, d, J=7.82 Hz), 7.89 (1H, d,J=7.32 Hz), 8.20 (1H, d, J=8.30 Hz)

Example 14 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-pyridylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 14 of Table 1)

According to the same procedure as in Example 12, using4-chloromethylpyridine hydrochloride instead of 2-chloromethylquinolinehydrochloride, the above-described compound (yield 81.0%) was obtainedas a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.59-1.65 (2H, m), 1.79-1.97 (6H, m), 2.16-2.28(2H, m), 3.22 (1H, ddd, J=11.23, 5.37, 3.91 Hz), 3.36-3.43 (1H, m), 3.85(3H, s), 4.55 (1H, d, J=15.63 Hz), 4.67 (1H, d, J=15.63 Hz), 4.80 (1H,m), 5.29 (1H, dd, J=9.76, 2.92 Hz), 6.85 (1H, d, J=8.30 Hz), 6.87-6.91(2H, m), 7.22 (2H, d, J=4.88 Hz), 8.58 (2H, d, J=4.88 Hz)

Example 15 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-naphthylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 15 of Table 1)

According to the same procedure as in Example 10, using2-bromomethylnaphthalene instead of methyl iodide, the above-describedcompound (yield 100%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.54-1.61 (2H, m), 1.78-1.94 (6H, m), 2.10-2.18(2H, m), 3.23 (1H, ddd, J=11.72, 5.37, 3.91 Hz), 3.35 (1H, ddd, J=11.72,10.25, 5.37 Hz), 3.84 (3H, s), 4.73 (1H, d, J=15.14 Hz), 4.78 (1H, m),4.82 (1H, d, J=15.14 Hz), 5.25 (1H, dd, J=9.76, 3.41 Hz), 6.83 (1H, d,J=8.30 Hz), 6.87 (1H, dd, J=8.30, 1.96 Hz), 6.90 (1H, d, J=1.96 Hz),7.46-7.51 (3H, m), 7.73 (1H, s), 7.80-7.84 (3H, m)

Example 16 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-pyridylmethyl)-2H-1,3-oxazin-2-one(Compound No. 16 of Table 1)

According to the same procedure as in Example 12, using2-chloromethylpyridine hydrochloride instead of 2-chloromethylquinolinehydrochloride, the above-described compound (yield 63.9%) was obtainedas a yellow oil. This compound was purified by flash chromatography(Al₂O₃; eluted by 3% ethyl acetate/methylene chloride).

¹H-NMR (400 MHz, CDCl₃) δ1.60 (2H, m), 1.79-1.90 (6H, m), 2.13-2.25 (2H,m), 3.41 (1H, ddd, J=11.72, 5.37, 3.91 Hz), 3.50-3.57 (1H, m), 3.84 (3H,s), 4.67 (1H, d, J=15.63 Hz), 4.74 (1H, d, J=15.63 Hz), 4.78 (1H, m),5.27 (1H, dd, J=9.77, 3.42 Hz), 6.84 (1H, d, J=8.30 Hz), 6.88 (1H, dd,J=8.30, 1.95 Hz), 6.91 (1H, d, J=1.95 Hz), 7.20-7.27 (1H, m), 7.39-7.41(1H, dd, J=6.35, 3.42 Hz), 7.66-7.71 (1H, m), 8.54 (1H, m)

Example 17 Synthesis of3-butyl-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 17 of Table 1)

According to the same procedure as in Example 10, using butyl iodideinstead of methyl iodide, the above-described compound (yield 83.3%) wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ0.95 (3H, t, J=7.33 Hz), 1.35 (2H, m, J=7.33Hz), 1.55-1.66 (4H, m), 1.79-1.96 (6H, m), 2.11-2.24 (2H, m), 3.26 (1H,ddd, J=11.72, 5.37, 3.91 Hz), 3.31-3.47 (3H, m), 3.84 (3H, s), 4.79 (1H,m), 5.20 (1H, dd, J=9.76, 2.93 Hz), 6.83 (1H, d, J=8.30 Hz), 6.87 (1H,dd, J=8.30, 1.47 Hz), 6.89 (1H, d, J=1.47 Hz)

Example 18 Synthesis of3-benzoyl-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 18 of Table 1)

According to the same procedure as in Example 10, using benzoyl chlorideinstead of methyl iodide, the above-described compound (yield 40.7%) wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.55-1.64 (2H, m), 1.80-1.96 (6H, m), 2.29-2.37(1H, m), 2.44-2.50 (1H, m), 3.79-3.85 (1H, m), 3.86 (3H, s), 4.13 (1H,ddd, J=12.69, 6.35, 3.42 Hz), 4.81 (1H, m), 5.42 (1H, dd, J=9.77, 2.45Hz), 6.88-6.95 (3H, m), 7.41 (2H, m), 7.48-7.50 (1H, m), 7.58 (2H, m)

Example 19 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(ethoxycarbonylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 19 of Table 1)

According to the same procedure as in Example 10, using ethylbromoacetate instead of methyl iodide, the above-described compound(yield 78.6%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.30 (3H, t, J=7.32 Hz), 1.59-1.62 (2H, m),1.81-1.97 (6H, m), 2.24 (2H, m), 3.34 (1H, ddd, J=10.74, 4.39, 4.39 Hz),3.58 (1H, m), 3.84 (3H, s), 4.07 (1H, d, J=17.06 Hz), 4.19 (1H, d,J=17.06 Hz), 4.23 (2H, q,J=7.32 Hz), 4.80 (1H, m), 5.30 (1H, t, J=6.35Hz), 6.85 (1H, d, J=8.30 Hz), 6.89 (1H, dd, J=8.30,1.96 Hz), 6.91 (1H,d, J=1.96 Hz)

Example 20 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-pyridylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 20 of Table 1)

According to the same procedure as in Example 12, using3-chloromethylpyridine hydrochloride instead of 2-chloromethylquinolinehydrochloride, the above-described compound (yield 59.2%) was obtainedas a yellow oil. This compound was purified by flash chromatography(Al₂O₃; eluted by gradient in range from ethyl acetate to 5%methanol/ethyl acetate).

¹H-NMR (400 MHz, CDCl₃) δ1.57-1.61 (2H, m), 1.77-1.95 (6H, m), 2.11-2.23(2H, m), 3.22 (1H, ddd, J=11.23, 5.37, 3.42 Hz), 3.39 (1H, ddd, J=11.23,11.23, 5.37 Hz), 3.83 (3H, s), 4.54 (1H, d, J=15.13 Hz), 4.66 (1H, d,J=15.13 Hz), 4.78 (1H, m), 5.24 (1H, dd, J=9.77, 2.93 Hz), 6.82-6.88(3H, m), 7.29 (1H, dd, J=7.81, 4.88 Hz), 7.73 (1H, d, J=7.81 Hz), 8.56(1H, dd, J=4.88, 1.47 Hz), 8.57 (1H, d, J=1.96 Hz)

Example 21 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3,6-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 21 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopentyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 6 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 99.4%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.65 (2H, m), 1.62 (3H, s), 1.81-1.99 (6H,m), 2.19 (1H, ddd, J=14.16, 11.23, 5.86 Hz), 2.33 (1H, ddd, J=14.16,4.88, 2.93 Hz), 2.90 (3H, s), 3.00 (1H, ddd, J=11.23, 11.23, 4.88 Hz),3.11 (1H, ddd, J=11.23, 5.86, 2.93 Hz), 3.84 (3H, s), 4.80 (1H, m), 6.81(1H, dd, J=8.30, 1.95 Hz), 6.85 (1H, d, J=8.30 Hz), 6.89 (1H, d, J=1.95Hz)

Example 22 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-methyl-3-(4-pyridylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 22 of Table 1)

According to the same procedure as in Example 21, using4-chloromethylpyridine hydrochloride instead of methyl iodide, theabove-described compound (yield 77.4%) was obtained as an orange solid.This compound was purified by flash chromatography (Al₂O₃; eluted bygradient in range from ethyl acetate to 5% methanol/ethyl acetate).

¹H-NMR (400 MHz, CDCl₃) δ1.59 (2H, m), 1.65 (3H, s), 1.81-1.94 (6H, m),2.22-2.28 (1H, m), 2.42 (1H, ddd, J=14.16, 4.88, 2.44 Hz), 3.00-3.06(2H, m), 4.36 (1H, d, J=16.11 Hz), 4.61 (1H, d, J=16.11 Hz), 4.78 (1H,m), 6.85 (2H, s), 6.90 (2H, d, J=5.86 Hz), 6.94 (1H, s), 8.43 (2H, d,J=5.86 Hz)

Example 23 Synthesis of6-(4-methoxy-3-phenethyloxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 23 of Table 1) (1) Synthesis of4-methoxy-3-phenethyloxybenzaldehyde

According to the same procedure as in Example 4(1), using phenethylalcohol, instead of cyclopropylcarbinol,4-methoxy-3-phenethyloxybenzaldehyde 2.88 g (yield 85.5%) was obtainedas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ3.19 (2H, t, J=7.33 Hz), 4.28 (2H, t, J=7.33Hz), 6.98 (1H, d, J=8.30 Hz), 7.23-7.35 (5H, m), 7.40 (1H, d, J=1.96Hz), 7.46 (1H, dd, J=8.30, 1.96 Hz), 9.83 (1H, s)

(2) Synthesis of3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)propiononitrile

According to the same procedure as in Example 1(1) using4-methoxy-3-phenethyloxybenzaldehyde, instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)propiononitrile was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.70 (1H, dd, J=16.60, 5.86 Hz), 2.75 (1H, dd,J=16.60, 6.83 Hz), 3.17 (2H, t, J=7.33 Hz), 3.87 (3H, s), 4.23 (1H, t,J=7.33 Hz), 4.95 (1H, m), 6.85-6.93 (3H, m), 7.22-7.34 (5H, m)

(3) Synthesis of6-(4-methoxy-3-phenethyloxyphenyl)-3,4,5,6-tetrahydro-2H-13-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)propiononitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 68.9%) was obtained as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ2.02-2.11 (1H, m), 2.13-2.19 (1H, m), 3.17 (2H,t, J=7.32 Hz), 3.35-3.41 (1H, m), 3.47 (1H, ddd, J=11.23, 11.23, 4.88Hz), 3.87 (3H, s), 4.20-4.24 (2H, m), 5.24 (1H, dd, J=9.76, 2.44 Hz),5.37 (1H, broad s), 6.86-6.92 (3H, m), 7.22-7.36 (5H, m)

Example 24 Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 24 of Table 1) (1) Synthesis of3-(2-indanyloxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using 2-indanolinstead of cyclopropylcarbinol, 3-(2-indanyloxy)-4-methoxybenzaldehyde(yield 62.6%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ3.25 (2H, dd, J=16.60, 3.42 Hz), 3.46 (2H, dd,J=16.60, 6.35 Hz), 3.90 (3H, s), 5.26 (1H, m), 6.98 (1H, d, J=8.30 Hz),7.17-7.21 (2H, m), 7.22-7.25 (2H, m), 7.46-7.49 (2H, m), 9.87 (1H, s)

(2) Synthesis of3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile

According to the same procedure as in Example 1(1), using3-(2-indanyloxy)-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.76 (2H, d, J=6.35 Hz), 3.23 (2H, dd, J=16.60,3.90 Hz), 3.39 (2H, ddd, J=16.60, 6.35, 2.93 Hz), 3.81 (3H, s), 4.98(1H, t, J=6.35 Hz), 5.20 (1H, m), 6.87 (1H, d, J=8.30 Hz), 6.93 (1H, dd,J=8.30,1.95 Hz), 7.01 (1H, d, J=1.95 Hz), 7.16-7.24 (4H, m)

(3) Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 74.2%) was obtained as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ2.08-2.16 (1H, m), 2.19-2.23 (1H, m), 3.24 (2H,dd, J=16.60, 3.42 Hz), 3.38 (2H, dd, J=16.60, 6.34 Hz), 3.38-3.68 (2H,m), 3.82 (3H, s), 5.21 (1H, m), 5.28 (1H, dd, J=10.25, 2.44 Hz), 5.43(1H, broad s), 6.87-6.99 (3H, m), 7.16-7.25 (4H, m)

Example 25 Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 25 of Table 1)

According to the same procedure as in Example 8, using the6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 24 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 100%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.16-2.23 (2H, m), 3.05 (3H, s), 3.23 (2H, dd,J=16.60, 2.93 Hz), 3.27 (1H, ddd, J=11.72, 5.37, 3.42 Hz), 3.37 (2H, dd,J=16.60, 6.35 Hz), 3.49 (1H, ddd, J=11.72, 11.72, 5.86 Hz), 3.81 (3H,s), 5.18-5.24 (2H, m), 6.86 (1H, d, J=8.30 Hz), 6.93 (1H, dd, J=8.30,1.96 Hz), 6.96 (1H, d, J=1.96 Hz), 7.15-7.19 (2H, m), 7.22-7.24 (2H, m)

Example 26 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 26 of Table 1) (1) Synthesis of3′-cyclopentyloxy-4′-methoxypropiophenone

According to the same procedure as in Example 6(1), using ethylmagnesium bromide instead of methyl magnesium bromide,3′-cyclopentyloxy-4′-methoxypropiophenone (yield 81.2%) was obtained asa brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.22 (3H, t, J=7.32 Hz), 1.57-1.68 (2H, m),1.76-2.04 (6H, m), 2.96 (2H, q, J=7.32 Hz), 3.91 (3H, s), 4.85 (1H, m),6.88 (1H, d, J=8.30 Hz), 7.53 (1H, d, J=1.96 Hz), 7.57 (1H, dd, J=8.30,1.96 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyvaleronitrile

According to the same procedure as in Example 1(1), using3′-cyclopentyloxy-4′-methoxypropiophenone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyvaleronitrile was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.83 (3H, t, J=7.32 Hz), 1.54-1.63 (2H, m),1.82-1.95 (6H, m), 2.01 (2H, q, J=7.32 Hz), 2.79 (1H, d, J=16.60 Hz),2.84 (1H, d, J=16.60 Hz), 3.85 (3H, s), 4.80 (1H, m), 6.85 (1H, d,J=8.30 Hz), 6.90 (1H, dd, J=8.30, 1.95 Hz), 6.99 (1H, d, J=1.95 Hz)

(3) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyvaleronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 21.8%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ0.84 (3H, t, J=7.33 Hz), 1.60 (2H, m),1.82-1.98 (8H, m), 2.14 (1H, ddd, J=11.72, 11.72, 5.37 Hz), 2.25 (1H, d,J=13.67 Hz), 3.01 (1H, ddd, J=11.72, 11.72, 4.39 Hz), 3.21-3.24 (1H, m),3.84 (3H, s), 4.79 (1H, m), 5.18 (1H, broad), 6.77-6.90 (3H, m)

Example 27 Synthesis of6-(3,4-dimethoxyphenyl)-6-(2-thiazolyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 27 of Table 1) (1) Synthesis of 3,4-dimethoxyphenyl2-thiazolyl ketone

A hexane solution of butyllithium (9.50 mM) was dissolved in drieddiethyl ether (6.5 ml) and cooled to −78° C. A solution of2-bromothiazole (1.03 g, 6.13 mM) in diethyl ether (0.5 ml) was droppedinto this solution. The solution was stirred at that temperature for 30minutes, then a solution of 3,4-dimethoxybenzonitrile (1.00 g, 6.13 mM)in diethyl ether (3.0 ml) was added and the resultant mixture stirredfor a further 6 hours. 1N Hydrochloric acid (20 ml) was poured into thesolution obtained, which was then warmed to room temperature and stirredfor 30 minutes, then a saturated sodium hydrogencarbonate solution wasadded to neutralize the solution and extraction was performed with ethylacetate. Next, the organic layer was washed with brine and dried overanhydrous magnesium sulfate, then the solvent was removed in vacuo toobtain a dark red solid residue. The residue was purified by flashchromatography (SiO₂: eluted by gradient from 50% hexane/methylenechloride to 25% hexane/methylene chloride). The solvent was removed invacuo and the resultant product was dried to obtain 3,4-dimethoxyphenyl2-thiazolyl ketone 0.71 g (yield 46.5%) as a red solid.

¹H-NMR (400 MHz, CDCl₃) δ3.99 (6H, s), 6.98 (1H, d, J=8.79 Hz), 7.70(1H, d, J=3.42 Hz), 8.02 (1H, d, J=1.96 Hz), 8.08 (1H, d, J=3.42 Hz),8.43 (1H, dd, J=8.79, 1.96 Hz)

(2) Synthesis of3-(3,4-dimethoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrile

According to the same procedure as in Example 1, using3,4-dimethoxyphenyl 2-thiazolyl ketone instead of3,4-dimethoxybenzaldehyde,3-(3,4-dimethoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ3.40 (1H, d, J=16.60 Hz), 3.51 (1H, d, J=16.60Hz), 3.87 (6H, s), 4.05 (1H, broad s), 6.85 (1H, d, J=8.30 Hz), 7.05(1H, dd, J=8.30, 2.44 Hz), 7.13 (1H, d, J=2.44 Hz), 7.36 (1H, d, J=3,42Hz), 7.76 (1H, d, J=3,42 Hz)

(3) Synthesis of6-(3,4-dimethoxyphenyl)-6-(2-thiazolyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3,4-dimethoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrile insteadof 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 38.3%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.65 (1H, ddd, J=14.16, 7.82, 5.86 Hz), 2.97(1H, ddd, J=14.16, 5.86, 5.86 Hz), 3.24-3.31 (1H, m), 3.34-3.40 (1H, m),3.86 (3H, s), 3.88 (3H, s), 5.53 (1H, broad s), 6.84 (1H, d, J=8.30 Hz),7.08 (1H, dd, J=8.30, 1.95 Hz), 7.12 (1H, d, J=1.95 Hz), 7.35 (1H, d,J=2.93 Hz), 7.77 (1H, d, J=2.93 Hz)

Example 28 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 28 of Table 1)

According to the same procedure as in Example 10, using ethyl iodideinstead of methyl iodide, the above-described compound (yield 98.1%) wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.20 (3H, t, J=7.33 Hz), 1.26-1.66 (2H, m),1.78-1.96 (6H, m), 2.11-2.25 (2H, m), 3.27 (1H, ddd, J=11.23, 5.37, 3.42Hz), 3.41-3.47 (1H, m), 3,44 (2H, q, J=7.33 Hz), 3.84 (3H, s), 4.79 (1H,m), 5.20 (1H, dd, J=9.77, 2.93 Hz), 6.83-6.89 (3H, m)

Example 29 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-thienyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 29 of Table 1) (1)Synthesis of 3-cyclopentyloxy-4-methoxyphenyl 2-thienyl ketone

According to the same procedure as in Example 7(1), using2-thienyllithium instead of phenyllithium,3-cyclopentyloxy-4-methoxyphenyl 2-thienyl ketone (yield 51.3%) wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.54-1.66 (2H, m), 1.80-2.03 (6H, m), 3.93 (3H,s), 4.85 (1H, m), 6.93 (1H, d, J=8.30 Hz), 7.17 (1H, dd, J=4.40 Hz),7.46 (1H, d, J=1.95 Hz), 7.54 (1H, dd, J=8.30, 1.95 Hz), 7.68 (1H, d,J=4.40 Hz), 7.69 (1H, d, J=4.40 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-thienyl)propiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxyphenyl 2-thienyl ketone instead of3cyclopentyloxy-4-methoxyphenyl/-3-hydroxy-3-(2-thienyl)propiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.53-1.61 (2H, m), 1.77-1.91 (6H, m), 3.26 (1H,d, J=16.60 Hz), 3.31 (1H, d, J=16.60 Hz), 3.85 (3H, s), 4.74 (1H, m),6.85 (1H, d, J=8.30 Hz), 6.96 (4H, m), 7.31 (1H, dd, J=4.88, 0.98 Hz)

(3) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-thienyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-thienyl)propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 35.4%) was obtained as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ1.59-1.61 (2H, m), 1.81-1.91 (6H, m), 2.66 (2H,t, J=5.86 Hz), 3.20-3.26 (1H, m), 3.35 (1H, ddd, J=11.23, 5.86, 2.44Hz), 3.84 (3H, s), 4.76 (1H, m), 5.46 (1H, broad s), 6.85 (1H, d, J=8.30Hz), 6.94-6.97 (3H, m), 6.99 (1H, d, J=1.95 Hz), 7.28 (1H, dd,J=3.42,3.42 Hz)

Example 30 Synthesis of6-butyl-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5 6-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 30 of Table 1) (1) Synthesis of3′-cyclopentyloxy-4′-methoxyvaleriophenone

According to the same procedure as in Example 7(1), using butyllithiuminstead of phenyllithium, 3′-cyclopentyloxy-4′-methoxyvaleriophenone(yield 78.9%) was obtained as a light green oil.

¹H-NMR (400 MHz, CDCl₃) δ0.95 (3H, t, J=7.32 Hz), 1.41 (2H, m),1.60-1.64 (2H, m), 1.71 (2H, m), 1.79-2.00 (6H, m), 2.91 (2H, t, J=7.32Hz), 3.90 (3H, s), 4.85 (1H, m), 6.87 (1H, d, J=8.30 Hz), 7.53 (1H, d,J=1.95 Hz), 7.56 (1H, dd, J=8.30, 1.95 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyheptanonitrile

According to the same procedure as in Example 1(1), using3′-cyclopentyloxy-4′-methoxyvaleriophenone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyheptanonitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.86 (3H, t, J=7.32 Hz), 1.11-1.34 (4H, m),1.54-1.63 (2H, m), 1.79-1.99 (8H, m), 2.78 (1H, d, J=16.60 Hz), 2.83(1H, d, J=16.60 Hz), 3.85 (3H, s), 4.80 (1H, m), 6.85 (1H, d, J=8.30Hz), 6.90 (1H, dd, J=8.30, 2.44 Hz), 6.98 (1H, d, J=2.44 Hz)

(3) Synthesis of6-butyl-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxyheptanonitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 40.6%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ0.82 (3H, t, J=7.32 Hz), 1.19-1.60 (6H, m),1.73-1.93 (8H, m), 2.13 (1H, ddd, J=14.16, 11.72, 5.37 Hz), 2.22-2.25(1H, m), 2.99 (1H, ddd, J=11.72, 11.72, 4.40 Hz), 3.11-3.21 (1H, m),3.84 (3H, s), 4.79 (1H, m), 5.75 (1H, broad), 6.79 (1H, dd, J=8.30, 1.95Hz), 6.84 (1H, d, J=1.95 Hz), 6.85 (1H, d, J=8.30 Hz)

Example 31 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-thiazolyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 31 of Table 1) (1) Synthesis of3-cyclopentyloxy-4-methoxybenzonitrile

3-cyclopentyloxy-4-methoxybenzaldehyde (13.00 g, 59.02 mM) andhydroxylamine hydrochloride (8.46 g, 118.04 mM) were dissolved inpyridine (120 ml) and the resultant mixture was heated to reflux for 23hours. The solution obtained was cooled to room temperature, water (100ml) was added, then the solution was extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, then thesolvent was removed in vacuo to obtain a green oily residue. The residuewas purified by flash chromatography (SiO₂: eluted by 20% ethylacetate/hexane). The solvent was removed in vacuo and the resultantproduct was dried to obtain 3-cyclopentyloxy-4-methoxybenzaldehyde oxime14.57 g as a colorless oil. The 3-cyclopentyloxy-4-methoxybenzaldehydeoxime (14.57 g) thus obtained was dissolved in acetic acid (130 ml) andthe resultant mixture was heated to reflux for 22 hours. The solutionobtained was ice cooled, then a saturated sodium hydrogencarbonatesolution was added to neutralize it. The solution was extracted withethyl acetate, the organic layer was dried over anhydrous magnesiumsulfate, and the solvent was removed in vacuo to obtain a red solidresidue. The residue was purified by flash chromatography (SiO₂: elutedby 25% ethyl acetate/hexane). The solvent was removed in vacuo and theresult dried to obtain 3-cyclopentyloxy-4-methoxybenzonitrile 9.60 g(yield 75.2%) as a yellow-green oil.

¹H-NMR (400 MHz, CDCl₃) δ1.55-1.69 (2H, m), 1.79-2.05 (6H, m), 3.89 (3H,s), 4.76 (1H, m), 6.88 (1H, d, J=8.30 Hz), 7.07 (1H, d, J=1.96 Hz), 7.25(1H, dd, J=8.30, 1.96 Hz)

(2) Synthesis of 3-cyclopentyloxy-4-methoxyphenyl 2-thiazolyl ketone

According to the same procedure as in Example 27(1), using3-cyclopentyloxy-4-methoxybenzonitrile instead of3,4-dimethoxybenzonitrile, 3-cyclopentyloxy-4-methoxyphenyl 2-thiazolylketone (yield 67.0%) was obtained as a red oil.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.68 (2H, m), 1.81-2.07 (6H, m), 3.94 (3H,s), 4.90 (1H, m), 6.96 (1H, d, J=8.79 Hz), 7.68 (1H, d, J=2.93 Hz), 8.05(1H, d, J=1.95 Hz), 8.07 (1H, d, J=2.93 Hz), 8.36 (1H, dd, J=8.79, 1.95Hz)

(3) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxyphenyl 2-thiazolyl ketone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.54-1.62 (2H, m), 1.79-1.93 (6H, m), 3.38 (1H,d, J=16.60 Hz), 3.50 (1H, d, J=16.60 Hz), 3.73 (1H, broad s), 3.83 (3H,s), 4.75 (1H, m), 6.85 (1H, d, J=8.30 Hz), 7.03 (1H, dd, J=8.30, 2.44Hz), 7.09 (1H, d, J=2.44 Hz), 7.37 (1H, d, J=3,42 Hz), 7.77 (1H, d,J=3,42 Hz)

(4) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-thiazolyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-thiazolyl)propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 33.1%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.80 (2H, m), 1.85-1.93 (6H, m), 2.65 (1H,ddd, J=13.68, 7.33, 5.86 Hz), 2.91 (1H, ddd, J=13.68, 5.86, 5.86 Hz),3.24-3.26 (1H, m), 3.32-3.36 (1H, m), 3.82 (3H, s), 4.77 (1H, m), 6.57(1H, broad), 6.83 (1H, d, J=8.30 Hz), 7.06 (1H, dd, J=8.30,1.96 Hz),7.08 (1H, d, J=1.96 Hz), 7.34 (1H, d, J=3.42 Hz), 7.76 (1H, d, J=3.42Hz)

Example 32 Synthesis of 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-[2-(1-piperidyl)ethyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 32 of Table 1)

According to the same procedure as in Example 10, using1-(2-iodoethyl)piperidine instead of methyl iodide, the above-describedcompound (yield 78.2%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ1.43 (2H, m), 1.54-1.62 (6H, m), 1.80-1.96 (6H,m), 2.10-2.23 (2H, m), 2.44 (4H, m), 2.57 (2H, m), 3.38 (1H, ddd,J=11.72, 5.37, 3.90 Hz), 3.43-3.56 (3H, m), 3.84 (3H, s), 4.79 (1H, m),5.21 (1H, dd, J=9.28, 2.93 Hz), 6.83-6.89 (3H, m)

Example 33 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-[2-(4-morpholino)ethyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 33 of Table 1)

According to the same procedure as in Example 10, using 4-(2-iodoethyl)morpholine instead of methyl iodide, the above-described compound (yield49.9%) was obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.62 (2H, m), 1.80-1.96 (6H, m), 2.11-2.24(2H, m), 2.50 (4H, m), 2.59 (2H, t, J=6.35 Hz), 3.36 (1H, ddd,J=11.71,5.37, 4.39 Hz), 3.42-3.58 (1H, m), 3.53 (2H, t, J=6.35 Hz), 3.69(4H, t, J=4.39 Hz), 3.84 (3H, s), 4.79 (1H, m), 5.22 (1H, dd, J=9.76,2.93 Hz), 6.83-6.89 (3H, m)

Example 34 Synthesis of3-(1-acetyl-3-methyl-2-indolylmethyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 34 of Table 1)

According to the same procedure as in Example 10, using1-acetyl-2-iodomethyl-3-methylindole instead of methyl iodide, theabove-described compound (yield 35.2%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.56 (3H, s), 1.58-1.60 (2H, m), 1.81-1.92 (6H,m), 2.05-2.19 (2H, m), 2.34 (3H, s), 3.32 (1H, ddd, J=11.72, 5.38, 2.93Hz), 3,49 (1H, ddd, J=11.72, 10.75, 5.38 Hz), 3.83 (3H, s), 4.43 (1H, d,J=15.14 Hz), 4.73-4.76 (1H, m), 4.76 (1H, d, J=15.14 Hz), 5.19 (1H, dd,J=10.25, 2.44 Hz), 6.80-6.85 (3H, m), 7.11 (1H, dd, J=7.81, 6.84 Hz),7.20 (1H, dd, J=7.81, 6.84 Hz), 7.33 (1H, d, J=7.81 Hz), 7.53 (1H, d,J=7.81 Hz)

Example 35 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-furylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 35 of Table 1)

According to the same procedure as in Example 10, using2-iodomethylfuran instead of methyl iodide, the above-described compound(yield 94.1%) was obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.61 (2H, m), 1.78-1.96 (6H, m), 2.10-2.23(2H, m), 3.34 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3,44 (1H, ddd, J=11.72,11.72, 5.37 Hz), 3.84 (3H, s), 4.56 (1H, d, J=15.63 Hz), 4.62 (1H, d,J=15.63 Hz), 4.77 (1H, m), 5.21 (1H, dd, J=9.77, 2.93 Hz), 6.33-6.35(2H, m), 6.82-6.88 (3H, m), 7.38 (1H, d, J=0.97 Hz)

Example 36 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(3-pyridyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 36 of Table 1) (1) Synthesis of3-cyclopentyloxy-4-methoxyphenyl 3-pyridyl ketone

According to the same procedure as in Example 31(2), using3-bromopyridine instead of 2-bromothiazole,3-cyclopentyloxy-4-methoxyphenyl 3-pyridyl ketone (yield 77.7%) wasobtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.66 (2H, m), 1.80-2.04 (6H, m), 3.94 (3H,s), 4.85 (1H, m), 6.91 (1H, d, J=8.30 Hz), 7.36 (1H, dd, J=8.30, 1.95Hz), 7.44 (1H, dd, J=7.82, 4.89 Hz), 7.47 (1H, d, J=1.95 Hz), 8.08 (1H,ddd, J=7.82, 1.95, 1.95 Hz), 8.79 (1H, dd, J=4.89, 1.95 Hz), 8.97 (1H,d, J=1.95 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(3-pyridyl)propiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxyphenyl 3-pyridyl ketone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(3-pyridyl)propiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.59 (2H, m), 1.79-1.87 (6H, m), 3.23 (1H,d, J=16.60 Hz), 3.29 (1H, d, J=16.60 Hz), 3.85 (3H, s), 4.70 (1H, m),6.84-6.90 (3H, m), 7.30 (1H, dd, J=8.30, 4.88 Hz), 7.76 (1H, ddd,J=8.30, 1.95, 1.95 Hz), 8.54 (1H, dd, J=4.88, 1.95 Hz), 8.62 (1H, s)

(3) Synthesis of 6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(3-pyridyl)-3,45,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(3-pyridyl)propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile,above-described compound (yield 14.9%) was obtained as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ1.57 (2H, m), 1.79-1.87 (6H, m), 2.58 (1H, ddd,J=14.16, 7.33, 7.33 Hz), 2.70 (1H, ddd, J=14.16, 5.37, 5.37 Hz), 3.28(2H, m), 3.83 (3H, s), 4.73 (1H, m), 6.45 (1H, broad), 6.84 (1H, d,J=7.81 Hz), 6.89-6.92 (2H, m), 7.28 (1H, dd, J=8.30, 4.88 Hz), 7.76 (1H,dd, J=8.30, 1.95 Hz), 8.52 (1H, d, J=4.88 Hz), 8.64 (1H, d, J=1.95 Hz)

Example 37 Synthesis of 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-pyrazinylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (CompoundNo. 37 of Table 1)

According to the same procedure as in Example 10, using2-iodomethylpyrazine instead of methyl iodide, the above-describedcompound (yield 24.4%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.62 (2H, m), 1.78-1.96 (6H, m), 2.18-2.26(2H, m), 3.46 (1H, ddd, J=11.23, 5.37, 3.91 Hz), 3.60 (1H, ddd, J=11.23,11.23, 5.37 Hz), 3.84 (3H, s), 4.69 (1H, d, J=15.62 Hz), 4.76 (1H, d,J=15.62 Hz), 4.76-4.80 (1H, m), 5.29 (1H, dd, J=9.28, 3.42 Hz),6.83-6.90 (3H, m), 8.52 (2H, s), 8.71 (1H, s)

Example 38 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-thienylmethyl)-3,4.56-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 38 of Table 1)

According to the same procedure as in Example 10, using2-iodomethylthiophene instead of methyl iodide, the above-describedcompound (yield 42.4%) was obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.61 (2H, m), 1.78-1.97 (6H, m), 2.06-2.23 (2H,m), 3.30 (1H, m), 3.42 (1H, m), 3.84 (3H, s), 4.72 (1H, d, J=15.14 Hz),4.77 (1H, m), 4.78 (1H, d, J=15.14 Hz), 5.21 (1H, dd, J=9.76, 2.93 Hz),6.82-6.87 (3H, m), 6.97 (1H, dd, J=4.89, 3.42 Hz), 7.04 (1H, d, J=3.42Hz), 7.26 (1H, d, J=4.89 Hz)

Example 39 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-pyridyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 39 of Table 1) (1) Synthesis of3-cyclopentyloxy-4-methoxyphenyl 2-pyridyl ketone

According to the same procedure as in Example 31(2), using2-bromopyridine instead of 2-bromothiazole,3-cyclopentyloxy-4-methoxyphenyl 2-pyridyl ketone(yield 99.0%) wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.58-1.66 (2H, m), 1.80-2.02 (6H, m), 3.92 (3H,s), 4.86 (1H, m), 6.90 (1H, d, J=8.79 Hz), 7.47 (1H, ddd, J=7.81, 4.88,0.98 Hz), 7.72 (1H, d, J=1.96 Hz), 7.72 (1H, dd, J=8.79, 1.96 Hz), 7.89(1H, ddd, J=7.81, 7.81, 1.95 Hz), 7.98 (1H, d, J=7.81 Hz), 8.71 (1H, d,J=4.88 Hz)

(2) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-pyridyl)propiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentyloxy-4-methoxyphenyl 3-pyridyl ketone instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-pyridyl)propiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.58 (2H, m), 1.79-1.89 (6H, m), 3.26 (1H,d, J=16.60 Hz), 3.34 (1H, d, J=16.60 Hz), 3.82 (3H, s), 4.73 (1H, m),5.69 (1H, s), 6.82 (1H, d, J=8.31 Hz), 6.95 (1H, dd, J=8.31, 1.95 Hz),7.00 (1H, d, J=1.95 Hz), 7.25-7.29 (2H, m), 7.35 (1H, d, J=8.30 Hz),7.72 (1H, ddd, J=7.82, 7.82, 1.95 Hz), 8.59 (1H, d, J=4.89 Hz)

(3) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-6-(2-pyridyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3-(2-pyridyl)propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 11.6%) was obtained as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ1.57-1.59 (2H, m), 1.78-1.94 (6H, m), 2.63 (1H,ddd, J=14.16, 6.84, 6.84 Hz), 2.93 (1H, ddd, J=14.16, 5.86, 5.86 Hz),3.21-3.24 (2H, m), 3.79 (3H, s), 4.75 (1H, m), 6.20 (1H, broad), 6.79(1H, d, J=8.78 Hz), 7.04 (1H, dd, J=8.78, 2.45 Hz), 7.07 (1H, d, J=2.45Hz), 7.18 (1H, ddd, J=5.37, 5.37, 2.44 Hz), 7.65-7.70 (2H, m), 8.56 (1H,d, J=5.37 Hz)

Example 40 Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 40 of Table 1) (1) Synthesis of3-(2-indanyloxy)-4-methoxyacetophenone

According to the same procedure as in Example 6(1), using the3-(2-indanyloxy)-4-methoxybenzaldehyde produced in Example 24(1) insteadof 3-cyclopentyloxy-4-methoxybenzaldehyde,3-(2-indanyloxy)-4-methoxyacetophenone (yield 75.7%) was obtained as ayellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.57 (3H, s), 3.24 (2H, dd, J=16.60, 3.42 Hz),3.44 (1H, dd, J=16.60, 6.83 Hz), 3.88 (3H, s), 5.27 (1H, m), 6.89 (1H,d, J=8.79 Hz), 7.17-7.20 (2H, m), 7.22-7.25 (2H, m), 7.59 (1H, dd,J=8.79, 1.95 Hz), 7.60 (1H, d, J=1.95 Hz)

(2) Synthesis of3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]butyronitrile

According to the same procedure as in Example 1(1), using3-(2-indanyloxy)-4-methoxyacetophenone instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]butyronitrile was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.76 (3H, s), 2.26 (1H, broad s), 2.78 (1H, d,J=16.60 Hz), 2.83 (1H, d, J=16.60 Hz), 3.24 (2H, dd, J=16.60, 3.91 Hz),3.38 (2H, dd, J=16.60, 6.34 Hz), 3.82 (3H, s), 5.23 (1H, m), 6.87 (1H,d, J=8.30 Hz), 7.01 (1H, dd, J=8.30, 2.44 Hz), 7.12 (1H, d, J=2.44 Hz),7.14-7.25 (4H, m)

(3) Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]butyronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 45.6%) was obtained as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ1.67 (3H, s), 2.12 (1H, ddd, J=14.16, 10.74,5.37 Hz), 2.29 (1H, ddd, J=14.16, 4.88, 4.88 Hz), 3.05 (1H, ddd,J=10.74, 10.74, 4.88 Hz), 3.21 (2H, ddd, J=16.60, 6.84, 3.91 Hz),3.22-3.30 (1H, m), 3.37 (2H, ddd, J=16.60, 6.34, 1.95 Hz), 3.81 (3H, s),5.21 (1H, m), 5.55 (1H, broad s), 6.86 (1H, d, J=8.30 Hz), 6.91 (1H, dd,J=8.30, 1.95 Hz), 6.96 (1H, d, J=1.95 Hz), 7.15-7.23 (4H, m)

Example 41 Synthesis of6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 41 of Table 1) (1) Synthesis of4-methoxy-3-(5-phenylpentyloxy)benzaldehyde

According to the same procedure as in Example 4(1), using5-phenylpentanol instead of cyclopropylcarbinol,4-methoxy-3-(5-phenylpentyloxy)benzaldehyde (yield 81.4%) was obtainedas a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.47-1.59 (2H, m), 1.67-1.75 (2H, m), 1.87-1.94(2H, m), 2.65 (2H, t, J=7.81 Hz), 3.94 (3H, s), 4.07 (2H, t, J=6.83 Hz),6.96-7.56 (8H, m), 9.84 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(5-phenylpentyloxy)benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]propiononitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.50-1.53 (2H, m), 1.68-1.72 (2H, m), 1.83-1.90(2H, m), 2.64 (2H, t, J=7.32 Hz), 2.70 (1H, dd, J=16.60, 6.35 Hz), 2.72(1H, dd, J=16.60, 6.35 Hz), 3.85 (3H, s), 4.01 (2H, t, J=6.35 Hz), 4.96(1H, t, J=6.35 Hz), 6.85 (1H, d, J=8.30 Hz), 6.90 (1H, dd, J=8.30, 1.96Hz), 6.93 (1H, d, J=1.96 Hz), 7.18-7.30 (5H, m)

(3) Synthesis of6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 44.1%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.48-1.58 (2H, m), 1.67-1.74 (2H, m), 1.85-1.92(2H, m), 2.06-2.13 (1H, m), 2.17-2.19 (1H, m), 2.65 (2H, t, J=7.33 Hz),3.37-3.42 (1H, m), 3.44-3.51 (1H, m), 3.90 (3H, s), 4.01 (2H, t, J=6.84Hz), 5.26 (1H, dd, J=9.77, 2.44 Hz), 5.60 (1H, broad s), 6.84-6.91 (3H,m), 7.16-7.30 (5H, m)

Example 42 Synthesis of6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 42 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 41 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 75.9%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.49-1.56 (2H, m), 1.66-1.74 (2H, m), 1.84-1.92(2H, m), 2.14-2.21 (2H, m), 2.64 (2H, t, J=7.81 Hz), 3.04 (3H, s), 3.25(1H, ddd, J=11.72, 5.37, 3.42 Hz), 3.44-3.51 (1H, m), 3.85 (3H, s), 4.01(2H, t, J=6.83 Hz), 5.21 (1H, dd, J=9.76, 3.42 Hz), 6.83-6.90 (3H, m),7.16-7.29 (5H, m)

Example 43 Synthesis of3,6-dimethyl-6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 43 of Table 1)

According to the same procedure as in Example 8, using the6-[3-(2-indanyloxy)-4-methoxyphenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 40 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 98.7%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.64 (3H, s), 2.20 (1H, ddd, J=13.67, 10.74,5.86 Hz), 2.33 (1H, ddd, J=13.67, 4.88, 3,41 Hz), 2.93 (3H, s), 3.02(1H, ddd, J=11.72, 10.74, 4.88 Hz), 3.14 (1H, ddd, J=11.72, 5.86, 3,41Hz), 3.23 (2H, dd, J=16.60, 3.91 Hz), 3.38 (2H, ddd, J=16.60, 6.35, 6.35Hz), 3.81 (3H, s), 5.21 (1H, m), 6.86 (1H, d, J=8.30 Hz), 6.89 (1H, dd,J=8.30, 1.95 Hz), 6.94 (1H, d, J=1.95 Hz), 7.16-7.20 (2H, m), 7.22-7.23(2H, m)

Example 44 Synthesis of6-(4-methoxy-3-phenethyloxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 44 of Table 1)

According to the same procedure as in Example 8, using the6-(4-methoxy-3-phenethyloxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 23 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 91.0%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.11-2.18 (2H, m), 3.03 (3H, s), 3.16 (2H, t,J=7.81 Hz), 3.24 (1H, ddd, J=11.72, 5.37, 3,41 Hz), 3.46 (1H, ddd,J=11.72, 10.74, 5.86 Hz), 3.86 (3H, s), 4.21 (2H, ddd, J=7.81, 7.81,2.93 Hz), 5.18 (1H, dd, J=9.77, 3,41 Hz), 6.84-6.90 (3H, m), 7.22-7.34(5H, m)

Example 45 Synthesis of6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 45 of Table 1) (1) Synthesis of4-methoxy-3-(5-phenylpentyloxy)acetophenone

According to the same procedure as in Example 6(1), using the4-methoxy-3-(5-phenylpentyloxy)benzaldehyde produced in Example 41(1)instead of 3-cyclopentyloxy-4-methoxybenzaldehyde,4-methoxy-3-(5-phenylpentyloxy)acetophenone (yield 97.3%) was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.50-1.57 (2H, m), 1.67-1.73 (2H, m), 1.86-1.92(2H, m), 2.56 (3H, s), 2.65 (2H, t, J=7.82 Hz), 3.92 (3H, s), 4.07 (2H,t, J=6.83 Hz), 6.88 (1H, d, J=8.30 Hz), 7.16-7.30 (5H, m), 7.51 (1H, d,J=1.96 Hz), 7.56 (1H, dd, J=8.30, 1.96 Hz)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]butyronitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(5-phenylpentyloxy)acetophenone instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]butyronitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.50-1.59 (2H, m), 1.69-1.75 (2H, m), 1.75 (3H,s), 1.85-1.91 (2H, m), 2.20 (1H, broad s), 2.65 (2H, t, J=7.81 Hz), 2.76(1H, d, J=16.60 Hz), 2.82 (1H, d, J=16.60 Hz), 3.86 (3H, s), 4.02 (2H,t, J=6.83 Hz), 6.85 (1H, d, J=8.30 Hz), 6.96 (1H, dd, J=8.30, 1.95 Hz),7.05 (1H, d, J=1.95 Hz), 7.16-7.30 (5H, m)

(3) Synthesis of6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-(5-phenylpentyloxy)phenyl)]butyronitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 52.9%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.47-1.55 (2H, m), 1.65 (3H, s), 1.68-1.73 (2H,m), 1.85-1.91 (2H, m), 2.12 (1H, ddd, J=14.16, 10.25, 5.37 Hz), 2.29(1H, ddd, J=14.16, 4.40, 4.40 Hz), 2.64 (2H, t, J=7.32 Hz), 3.05 (1H,ddd, J=11.23, 10.25, 4.40 Hz), 3.25 (1H, ddd, J=11.23, 5.37, 4.40 Hz),3.85 (3H, s), 5.31 (1H, broad s), 6.85 (2H, s), 6.90 (1H, s), 7.15-7.29(5H, m)

Example 46 Synthesis of6-(4-methoxy-3-phenethyloxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 46 of Table 1) (1) Synthesis of4-methoxy-3-phenethyloxyacetophenone

According to the same procedure as in Example 6(1), using the4-methoxy-3-phenethyloxybenzaldehyde produced in Example 23(1) insteadof 3-cyclopentyloxy-4-methoxybenzaldehyde,4-methoxy-3-phenethyloxyacetophenone(yield 89.3%) was obtained as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.55 (3H, s), 3.18 (2H, t, J=7.32 Hz), 3.94(3H, s), 4.27 (2H, t, J=7.32 Hz), 6.90 (1H, d, J=8.30 Hz), 7.25-7.33(5H, m), 7.51 (1H, d, J=1.95 Hz), 7.58 (1H, dd, J=8.30, 1.95 Hz)

(2) Synthesis of3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)butyronitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-phenethyloxyacetophenone instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)butyronitrile was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.72 (3H, s), 2.74 (1H, d, J=16.60 Hz), 2.78(1H, d, J=16.60 Hz), 3.17 (2H, t, J=7.32 Hz), 3.87 (3H, s), 4.24 (2H, t,J=7.32 Hz), 6.86 (1H, d, J=8.30 Hz), 6.97 (1H, dd, J=8.30,1.95 Hz), 7.00(1H, d, J=1.95 Hz), 7.22-7.35 (5H, m)

(3) Synthesis of6-(4-methoxy-3-phenethyloxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-(4-methoxy-3-phenethyloxyphenyl)butyronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 74.6%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.63 (3H, s), 2.09 (1H, ddd, J=14.16, 11.24,5.37 Hz), 2.24 (1H, ddd, J=14.16, 4.40, 3.90 Hz), 3.01 (1H, ddd,J=11.24, 11.24, 4.40 Hz), 3.15 (2H, t, J=7.32 Hz), 3.20-3.25 (1H, m),3.86 (3H, s), 4.21 (2H, m), 5.66 (1H, broad s), 6.82-6.89 (3H, m),7.21-7.34 (5H, m)

Example 47 Synthesis of3,6-dimethyl-6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 47 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 45 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 86.0%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.47-1.57 (2H, m), 1.61 (3H, s), 1.65-1.73 (2H,m), 1.83-1.90 (2H, m), 2.18 (1H, ddd, J=13.67, 10.74, 5.86 Hz), 2.33(1H, ddd, J=13.67, 4.88, 3.42 Hz), 2.66 (2H, t, J=7.32 Hz), 2.90 (3H,s), 3.01 (1H, ddd, J=11.72, 10.74, 4.88 Hz), 3.12 (1H, ddd, J=11.72,5.86, 3.42 Hz), 3.85 (3H, s), 4.00 (2H, t, J=6.83 Hz), 6.81-6.88 (3H,m), 7.15-7.29 (5H, m)

Example 48 Synthesis of3.6-dimethyl-6-(4-methoxy-3-phenethyloxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 48 of Table 1)

According to the same procedure as in Example 8, using the6-(4-methoxy-3-phenethyloxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 46 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 71.0%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.60 (3H, s), 2.17 (1H, ddd, J=14.16, 11.23,5.86 Hz), 2.30 (1H, ddd, J=14.16, 4.88, 3.91 Hz), 2.89 (3H, s), 2.99(1H, ddd, J=11.23, 11.23, 4.88 Hz), 3.10 (1H, ddd, J=11.23, 5.86, 3.91Hz), 3.15 (2H, t, J=7.32 Hz), 3.86 (3H, s), 4.21 (2H, m), 6.85-6.86 (3H,m), 7.21-7.34 (5H, m)

Example 49 Synthesis of6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3-methyl-3,45,6-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 49 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 4 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 73.7%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.33-0.37 (2H, m), 0.62-0.67 (2H, m), 1.30-1.37(1H, m), 2.12-2.24 (2H, m), 3.04 (3H, s), 3.26 (1H, ddd, J=11.72, 5.86,3.42 Hz), 3.48 (1H, ddd, J=11.72, 10.26, 5.86 Hz), 3.85 (2H, d, J=6.83Hz), 3.88 (3H, s), 5.21 (1H, dd, J=9.77, 3.42 Hz), 6.85 (1H, d, J=8.30Hz), 6.86 (1H, dd, J=8.30, 1.47 Hz), 6.91 (1H, d, J=1.47 Hz)

Example 50 Synthesis of6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 50 of Table 1) (1) Synthesis of3-cyclopropylmethyloxy-4-methoxyacetophenone

According to the same procedure as in Example 6(1), using the3-cyclopropylmethyloxy-4-methoxybenzaldehyde produced in Example 4(1)instead of 3-cyclopentyloxy-4-methoxybenzaldehyde,3-cyclopropylmethyloxy-4-methoxyacetophenone (yield 92.9%) was obtainedas a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ0.35-0. 39 (2H, m) , 0.64-0.68 (2H, m),1.32-1.39 (1H, m), 2.56 (3H, s), 3.91 (2H, d, J=6.83 Hz), 3.95 (3H, s),6.89 (1H, d, J=8.79 Hz), 7.51 (1H, d, J=1.95 Hz), 7.57 (1H, dd,J=8.79,1.95 Hz)

(2) Synthesis of 3-( 3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile

According to the same procedure as in Example Example 1(1), using3-cyclopropylmethyloxy-4-methoxyacetophenone instead of3,4-dimethoxybenzaldehyde, 3- (3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.34-0.38 (2H, m) , 0.63-0.67 (2H, m),1.30-1.38 (1H, m), 1.76 (3H, s), 2.77 (1H, d, J=16.61 Hz), 2.83 (1H, d,J=16.61 Hz), 3.88 (3H, s), 3.88 (2H, d, J=6.83 Hz), 6.86 (1H, d, J=8.30Hz), 6.97 (1H, dd, J=8.30,2.44 Hz), 7.06 (1H, d, J=2.44 Hz)

(3) Synthesis of 6- (3-cyclopropylmethyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using 3-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3-hydroxybutyronitrile insteadof 3-(3,4-dimethoxyphenyl) -3-hydroxypropiononitrile, theabove-described compound (yield 58.8%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ0.33-0.37 (2H, m), 0.61-0.66 (2H, m), 1.29-1.34(1H, m), 1.66 (3H, s), 2.13 (1H, ddd, J=13.67,10.75, 5.37 Hz), 2.30 (1H,ddd, J=13.67, 4.88, 4.88 Hz), 3.06 (1H, ddd, J=10.75, 10.75, 4.88 Hz),3.23-3.28 (1H, m), 3.84-3.86 (2H, m), 3.87 (3H, s), 5.30 (1H, broad),6.86-6.91 (3H, m)

Example 51 Synthesis of 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-3,6-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 51 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopropylmethyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 50 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 94.7%) was obtained as a light brownoil.

¹H-NMR (400 MHz, CDCl₃) δ0.33-0.37 (2H, m), 0.61-0.66 (2H, m), 1.28-1.35(1H, m), 1.61 (3H, s), 2.19 (1H, ddd, J=13.68, 11.72, 5.86 Hz), 2.34(1H, ddd, J=13.68, 4.88, 3.42 Hz), 2.90 (3H, s), 3.02 (1H, ddd, J=11.72,11.72, 4.88 Hz), 3.12 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3.85 (2H, d,J=6.83 Hz), 3.87 (3H, s), 6.85-6.90 (3H, m)

Example 52 Synthesis of6-(3-butoxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 52 of Table 1) (1) Synthesis of3-butoxy-4-methoxyacetophenone

According to the same procedure as in Example 6(1), using3-butoxy-4-methoxybenzaldehyde instead of3-cyclopentyloxy-4-methoxybenzaldehyde, 3-butoxy-4-methoxyacetophenone(yield 97.3%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.99 (3H, t, J=7.32 Hz), 1.48-1.58 (2H, m),1.81-1.88 (2H, m), 2.56 (3H, s), 3.93 (3H, s), 4.08 (2H, t, J=6.84 Hz),6.88 (1H, d, J=8.30 Hz), 7.52 (1H, d, J=1.96 Hz), 7.56 (1H, dd, J=8.30,1.96 Hz)

(2) Synthesis of 3-(3-butoxy-4-methoxyphenyl)-3-hydroxybutyronitrile

According to the same procedure as in Example 1(1), using3-butoxy-4-methoxyacetophenone instead of 3,4-dimethoxybenzaldehyde,3-(3-butoxy-4-methoxyphenyl)-3-hydroxybutyronitrile was obtained as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.99 (3H, t, J=6.83 Hz), 1.51 (2H, m), 1.76(3H, s), 1.84 (2H, m), 2.77 (1H, d, J=16.60 Hz), 2.83 (1H, d, J=16.60Hz), 3.86 (3H, s), 4.04 (2H, t, J=6.83 Hz), 6.85 (1H, d, J=8.30 Hz),6.97 (1H, dd, J=8.30,2.44 Hz), 7.07 (1H, d, J=2.44 Hz)

(3) Synthesis of6-(3-butoxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-butoxy-4-methoxyphenyl)-3-hydroxybutyronitrile instead of3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 32.6%) was obtained as a brown solid.

¹H-NMR (400 MHz, CDCl₃) δ0.97 (3H, t, J=7.32 Hz), 1.49 (2H, m), 1.66(3H, s), 1.82 (2H, m), 2.13 (1H, ddd, J=13.67, 10.25, 5.38 Hz), 2.31(1H, ddd, J=13.67, 4.40, 4.40 Hz), 3.06 (1H, ddd, J=11.23, 10.25, 4.40Hz), 3.23-3.30 (1H, m), 3.86 (3H, s), 4.02 (2H, t, J=6.84 Hz), 5.15 (1H,broad s), 6.85-6.91 (3H, m)

Example 53 Synthesis of6-(3-butoxy-4-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 53 of Table 1)

According to the same procedure as in Example 8, using the6-(3-butoxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 3 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 81.7%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.98 (3H, t, J=7.32 Hz), 1.45-1.54 (2H, m),1.79-1.85 (2H, m), 2.13-2.24 (2H, m), 3.04 (3H, s), 3.26 (1H, ddd,J=11.23, 5.85, 3.42 Hz), 3.48 (1H, m), 3.86 (3H, s), 4.02 (2H, t, J=6.83Hz), 5.21 (1H, dd, J=9.76, 3,41 Hz), 6.83-6.91 (3H, m)

Example 54 Synthesis of6-(3-butoxy-4-methoxyphenyl)-3,6-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 54 of Table 1)

According to the same procedure as in Example 8, using the6-(3-butoxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 52 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 92.1%) was obtained as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ0.97 (3H, t, J=7.33 Hz), 1.45-1.54 (2H, m),1.62 (3H, s), 1.78-1.85 (2H, m), 2.19 (1H, ddd, J=13.67,11.72, 5.86 Hz),2.34 (1H, ddd, J=13.67, 4.88, 3.42 Hz), 2.90 (3H, s), 3.02 (1H, ddd,J=11.72, 11.72, 4.88 Hz), 3.12 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3.86(3H, s), 4.02 (2H, t, J=6.83 Hz), 6.82 (1H, dd, J=8.30, 1.95 Hz), 6.85(1H, d, J=8.30 Hz), 6.90 (1H, d, J=1.95 Hz)

Example 55 Synthesis of6-[4-methoxy-3-[2-(2-pyridyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 55 of Table 1) (1) Synthesis of4-methoxy-3-[2-(2-pyridyl)ethoxy]benzaldehyde

According to the same procedure as in Example 4(1), using2-(2-pyridyl)ethanol instead of cyclopropylcarbinol,4-methoxy-3-[2-(2-pyridyl)ethoxy]benzaldehyde (yield 83.7%) was obtainedas a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ3.36 (2H, t, J=7.32 Hz), 3.94 (3H, s), 4.48(2H, t, J=7.32 Hz), 6.97 (1H, d, J=7.81 Hz), 7.16 (1H, dd, J=7.32,4.88Hz), 7.29 (1H, d, J=7.81 Hz), 7.45-7.47 (2H, m), 7.63 (1H, ddd,J=7.81,7.81,1.95 Hz),8.56 (1H, d, J=4.88 Hz), 9.83 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-[2-(2-pyridyl)ethoxy]phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-[2-(2-pyridyl)ethoxy]benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-[2-(2-pyridyl)ethoxy]phenyl]propiononitrile wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.68-2.79 (2H, m), 3.14 (1H, broad s), 3.30(2H, t, J=7.32 Hz), 3.83 (3H, s), 4.39 (2H, t, J=7.32 Hz), 4.96 (1H, t,J=6.35 Hz), 6.85 (1H, d, J=8.30 Hz), 6.93 (1H, dd, J=8.30, 1.95 Hz),6.98 (1H, d, J=1.95 Hz), 7.15 (1H, dd, J=7.82, 4.88 Hz), 7.29 (1H, d,J=7.82 Hz), 7.63 (1H, ddd, J=7.82, 7.82, 1.96 Hz), 8.51 (1H, m)

(3) Synthesis of6-[4-methoxy-3-[2-(2-pyridyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-[2-(2-pyridyl)ethoxy]phenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 25.9%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ2.04-2.17 (2H, m), 3.33 (2H, t, J=7.32 Hz),3.39-3.69 (2H, m), 3.84 (3H, s), 4.42 (2H, t, J=7.32 Hz), 5.27 (1H, m),6.86 (1H, d, J=8.31 Hz), 6.91-6.94 (2H, m), 7.15 (1H, m), 7.30 (1H, d,J=7.82 Hz), 7.62 (1H, t, J=7.82 Hz), 8.56 (1H, d, J=3.90 Hz)

Example 56 Synthesis of6-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 56 of Table 1) (1) Synthesis of4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]benzaldehyde

According to the same procedure as in Example 4(1), using1-phenylcyclopropylmethanol instead of cyclopropylcarbinol,4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]benzaldehyde (yield 74.8%)was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.00-1.02 (2H, m), 1.04-1.07 (2H, m), 3.90 (3H,s), 4.13 (2H, s), 6.93 (1H, d, J=7.81 Hz), 7.19-7.23 (1H, m), 7.28-7.31(3H, m), 7.41-7.45 (3H, m), 9.79 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]propiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ0.97-1.00 (2H, m), 1.02-1.05 (2H, m), 2.38 (1H,broad s), 2.61 (1H, dd, J=16.60, 5.86 Hz), 2.66 (1H, dd, J=16.60, 5.86Hz), 3.79 (3H, s), 4.09 (2H, s), 4.83 (1H, t, J=5.86 Hz), 6.73 (1H, d,J=1.96 Hz), 6.81 (1H, d, J=8.30 Hz), 6.84 (1H, dd, J=8.30, 1.96 Hz),7.18-7.22 (1H, m), 7.25-7.31 (2H, m), 7.42-7.45 (2H, m)

(3) Synthesis of6-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]-3,4,56-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 55.5%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.97-1.00 (2H, m), 1.03-1.06 (2H, m), 1.98-2.05(1H, m), 2.08-2.14 (1H, m), 3.33-3.37 (1H, m), 3.40-3,47 (1H, m), 3.80(3H, s), 4.10 (2H, s), 5.19 (1H, dd, J=10.24, 2.93 Hz), 5.65 (1H, broads), 6.79 (1H, d, J=1.95 Hz), 6.83 (1H, d, J=8.30 Hz), 6.86 (1H, dd,J=8.30, 1.95 Hz), 7.18-7.21 (1H, m), 7.27-7.31 (2H, m), 7.43-7.45 (2H,m)

Example 57 Synthesis of6-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 57 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 56 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 91.2%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ0.97-1.00 (2H, m), 1.03-1.06 (2H, m), 2.06-2.14(2H, m), 3.03 (3H, s), 3.22 (1H, ddd, J=11.72,5.37,2.93 Hz), 3.44 (1H,ddd, J=11.72,10.74,5.85 Hz), 3.79 (3H, s), 4.09 (2H, s), 5.14 (2H, dd,J=9.77,2.93 Hz), 6.78 (1H, d, J=1.96 Hz), 6.81 (1H, d, J=8.30 Hz), 6.85(1H, dd, J=8.30,1.96 Hz), 7.18-7.22 (1H, m), 7.27-7.31 (2H, m),7.42-7.45 (2H, m)

Example 58 Synthesis of6-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 58 of Table 1) (1) Synthesis of3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using dibenzosuberolinstead of cyclopropylcarbinol,3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxybenzaldehyde(yield 51.9%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ3.15-3.21 (2H, m), 3.55-3.62 (2H, m), 3.96 (3H,s), 6.37 (1H, s), 6.98 (1H, d, J=8.31 Hz), 7.11-7.22 (6H, m), 7.34 (1H,d, J=1.95 Hz), 7.43-7.47 (3H, m), 9.74 (1H, s)

(2) Synthesis of3-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclophenten-5-yloxy)-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxybenzaldehydeinstead of 3,4-dimethoxybenzaldehyde,3-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclophenten-5-yloxy)-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.09 (1H, d, J=2.93 Hz), 2.49 (1H, dd,J=16.60,5.86 Hz), 2.56 (1H, dd, J=16.60,6.83 Hz), 3.10-3.16 (2H, m),3.60-3.66 (2H, m),3.89 (3H, s), 4.81 (1H, m), 6.17 (1H, s), 6.71 (1H, d,J=1.95 Hz), 6.88 (1H, d, J=8.30 Hz), 6.94 (1H, dd, J=8.30,1.95 Hz),7.11-7.22 (6H, m), 7.38 (2H, dd, J=7.32,3,41 Hz)

(3) Synthesis of6-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclophenten-5-yloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 22.6%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.73-1.88 (1H, m), 1.89-1.95 (1H, m), 3.05-3.14(3H, m), 3.24 (1H, ddd, J=11.23,11.23,4.89 Hz), 3.57-3.68 (2H, m), 3.84(3H, s), 5.08 (1H, dd, J=9.76,2.93 Hz), 6.19 (1H, s), 6.62 (1H, broads), 6.69 (1H, d, J=1.96 Hz), 6.84 (1H, d, J=8.30 Hz), 6.90 (1H, dd,J=8.30,1.96 Hz), 7.08-7.19 (6H, m), 7.38 (2H, d, J=7.32 Hz)

Example 59 Synthesis of6-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxyphenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 59 of Table 1)

According to the same procedure as in Example 8, using the6-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 58 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 77.0%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.89-1.97 (1H, m), 1.99-2.05 (1H, m), 2.98 (3H,s), 3.08-3.18 (3H, m), 3.34 (1H, ddd, J=11.23,9.77,5.37 Hz), 3.57-3.68(2H, m), 3.88 (3H, s), 5.08 (1H, dd, J=9.28,2.45 Hz), 6.19 (1H, s), 6.68(1H, d, J=1.95 Hz), 6.87 (1H, d, J=8.30 Hz), 6.92 (1H, dd, J=8.30,1.95Hz), 7.10-7.22 (6H, m), 7.39 (2H, d, J=7.32 Hz)

Example 60 Synthesis of6-[3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 60 of Table 1) (1) Synthesis of3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using3-(4-benzyl-1-piperazinyl)propanol instead of cyclopropylcarbinol,3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxybenzaldehyde (yield52.2%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.04 (2H, m), 2.46-2.55 (8H, m), 2.53 (2H, t,J=7.32 Hz), 3.52 (2H, s), 3.94 (3H, s), 4.14 (2H, t, J=6.35 Hz), 6.97(1H, d, J=8.30 Hz), 7.28-7.33 (5H, m), 7.42 (1H, d, J=1.46 Hz),7.55-7.57 (1H, m), 9.84 (1H, s)

(2) Synthesis of3-[3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.02 (2H, m), 2.45-2.54 (8H, m), 2.52 (2H, t,J=6.84 Hz), 2.74-2.77 (2H, m), 3.51 (2H, s), 3.85 (3H, s), 4.07 (2H, t,J=6.83 Hz), 4.97 (1H, m), 6.86 (1H, d, J=8.30 Hz), 6.91 (1H, dd,J=8.30,1.95 Hz), 6.97 (1H, d, J=1.95 Hz), 7.30-7.32 (5H, m)

(3) Synthesis of6-[3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-[3-(4-benzyl-1-piperazinyl)propoxy]-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 14.8%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.03 (2H, m), 2.04-2.12 (1H, m), 2.15-2.19 (1H,m), 2.35-2.56 (8H, m), 2.54 (2H, t, J=6.83 Hz), 3.36-3,49 (2H, m), 3.51(2H, s), 3.85 (3H, S), 4.07 (2H, t, J=6.35 Hz), 5.24 (1H, dd,J=9.77,2.44 Hz), 6.26 (1H, broad s), 6.85 (1H, d, J=8.30 Hz), 6.89 (1H,dd, J=8.30,1.95 Hz), 6.92 (1H, d, J=1.95 Hz), 7.23-7.32 (5H, m)

Example 61 Synthesis of6-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 61 of Table 1) (1) Synthesis of3-cyclobutylmethyloxy-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), usingcyclobutylmethanol instead of cyclopropylcarbinol,3-cyclobutylmethyloxy-4-methoxybenzaldehyde (yield 77.1%) was obtainedas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.84-2.01 (4H, m), 2.14-2.22 (2H, m), 2.86 (1H,m), 3.94 (3H, s), 4.06 (2H, d, J=6.83 Hz), 6.97 (1H, d, J=8.30 Hz), 7.41(1H, d, J=1.95 Hz), 7.44 (1H, dd, J=8.30,1.95 Hz), 9.85 (1H, s)

(2) Synthesis of3-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-cyclobutylmethyloxy-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.06 (1H, d, J=6.35 Hz), 1.82-2.00 (4H, m),2.13-2.20 (2H, m), 2.73 (1H, dd, J=16.60,6.35 Hz), 2.78 (1H, dd,J=16.60,6.35 Hz), 2.84 (1H, m,J=6.84 Hz), 3.85 (3H, s), 4.01 (2H, d,J=6.84 Hz), 4.98 (1H, t, J=6.35 Hz), 6.86 (1H, d, J=8.30 Hz), 6.91 (1H,dd, J=8.30,1.96 Hz), 6.95 (1H, d, J=1.96 Hz)

(3) Synthesis of6-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 55.7%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.83-1.98 (4H, m), 2.08-2.22 (4H, m), 2.83 (1H,m), 3,40 (1H, ddd, J=11.23,5.86,3.42 Hz), 3,49 (1H, ddd,J=11.23,11.23,5.37 Hz), 3.86 (3H, s), 4.01 (2H, d, J=6.84 Hz), 5.26 (1H,broad s), 5.27 (1H, dd, J=9.77,2.93 Hz), 6.85 (1H, d, J=8.30 Hz), 6.88(1H, dd, J=8.30,1.95 Hz), 6.93 (1H, d, J=1.95 Hz)

Example 62 Synthesis of6-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 62 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclobutylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 61 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 67.4%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.80-2.00 (4H, m), 2.11-2.24 (4H, m), 2.83 (1H,m), 3.04 (3H, s), 3.26 (1H, ddd, J=11.23,4.88,3,41 Hz), 3.48 (1H, ddd,J=11.23,10.26,5.86 Hz), 3.85 (3H, s), 4.00 (2H, d, J=6.83 Hz), 5.21 (1H,dd, J=9.28,2.93 Hz), 6.84 (1H, d, J=8.30 Hz), 6.85-6.92 (2H, m)

Example 63 Synthesis of6-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 63 of Table 1) (1) Synthesis of4-methoxy-3-[(1-methylcyclopropyl)methyloxy]benzaldehyde

According to the same procedure as in Example 4(1), using1-methylcyclopropylcarbinol instead of cyclopropylcarbinol,4-methoxy-3-[(1-methylcyclopropyl)methyloxy]benzaldehyde (yield 65.0%)was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.45-0.47 (2H, m), 0.56-0.57 (2H, m), 1.27 (3H,s), 3.84 (2H, s), 3.95 (3H, s), 6.97 (1H, d, J=8.30 Hz), 7.37 (1H,broad), 7.45 (1H, dd, J=8.30,1.46 Hz), 9.83 (1H, s)

(2) Synthesis of3-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-[(1-methylcyclopropyl)methyloxy]benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3-hydroxypropiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.43-0.45 (2H, m), 0.54-0.57 (2H, m), 1.26 (3H,s), 1.61 (1H, broad s), 2.72 (1H, dd, J=16.60,6.35 Hz), 2.77 (1H, dd,J=16.60,6.35 Hz), 3.79 (2H, s), 3.86 (3H, s), 4.97 (1H, t, J=6.35 Hz),6.85-6.93 (3H, m)

(3) Synthesis of6-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 37.5%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ0.42-0.45 (2H, m), 0.54-0.56 (2H, m), 1.26 (3H,s), 2.05-2.12 (1H, m), 2.15-2.20 (1H, m), 3.39 (1H, ddd,J=11.23,5.86,3.42 Hz), 3,47 (1H, ddd, J=11.23,10.74,4.88 Hz), 3.79 (2H,s), 3.87 (3H, s), 5.25 (1H, dd, J=10.26,2.93 Hz), 5.94 (1H, broad s),6.85-6.90 (3H, m)

Example 64 Synthesis of6-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 64 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-[(1-methylcyclopropyl)methyloxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 63 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 87.9%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.42-0.44 (2H, m), 0.53-0.56 (2H, m), 1.26 (3H,s), 2.13-2.21 (2H, m), 3.04 (3H, s), 3.26 (1H, ddd, J=11.72,5.38,3.42Hz), 3.48 (1H, ddd, J=11.72,10.74,5.86 Hz), 3.78 (2H, s), 3.86 (3H, s),5.20 (1H, dd, J=9.77,3.42 Hz), 6.83-6.90 (3H, m)

Example 65 Synthesis of6-[4-methoxy-3-(2-methylpropoxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 65 of Table 1) (1) Synthesis of4-methoxy-3-(2-methylpropoxy)benzaldehyde

According to the same procedure as in Example 4(1), using isobutanolinstead of cyclopropylcarbinol,4-methoxy-3-(2-methylpropoxy)benzaldehyde (yield 75.8%) was obtained asa yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.05 (6H, d, J=6.83 Hz), 2.19 (1H, m, J=6.83Hz), 3.83 (2H, d, J=6.83 Hz), 3.95 (3H, s), 6.97 (1H, d, J=7.81 Hz),7.40 (1H, d, J=1.46 Hz), 7.44 (1H, dd, J=7.81,1.46 Hz), 9.84 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-(2-methylpropoxy)phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(2-methylpropoxy)benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-(2-methylpropoxy)phenyl]propiononitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.04 (6H, d, J=6.84 Hz), 2.17 (1H, m,J=6.84Hz), 2.73 (1H, dd, J=16.60,6.35 Hz), 2.79 (1H, dd, J=16.60,6.35 Hz),3.78 (2H, d, J=6.84 Hz), 3.86 (3H, s), 4.98 (1H, t, J=6.35 Hz), 6.86(1H, d, J=8.30 Hz), 6.91 (1H, dd, J=8.30,1.95 Hz), 6.94 (1H, d, J=1.95Hz)

(3) Synthesis of6-[4-methoxy-3-(2-methylpropoxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-(2-methylpropoxy)phenyl]propiononitrile insteadof 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 65.7%) was obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.04 (6H, d, J=6.84 Hz), 2.06-2.22 (3H, m),3.37-3.52 (2H, m), 3.78 (2H, d, J=6.83 Hz), 3.87 (3H, s), 5.26 (1H, dd,J=10.25,2.93 Hz), 5.91 (1H, broad s), 6.85-6.91 (3H, m)

Example 66 Synthesis of6-[4-methoxy-3-(2-methylpropoxy)phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 66 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-(2-methylpropoxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneof Example 65 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 93.6%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.03 (6H, d, J=6.34 Hz), 2.13-2.21 (3H, m),3.04 (3H, s), 3.26 (1H, ddd, J=11.72,5.86,3.42 Hz), 3.48 (1H, ddd,J=11.72,10.25,6.34 Hz), 3.77 (2H, d, J=6.83 Hz), 3.86 (3H, s), 5.21 (1H,dd, J=9.76,3.90 Hz), 6.85-6.91 (2H, m), 7.36 (1H, s)

Example 67 Synthesis of6-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 67 of Table 1) (1) Synthesis of4-methoxy-3-[2-(1-naphthyl)ethoxy]benzaldehyde

According to the same procedure as in Example 4(1), using2-(1-naphthyl)ethanol instead of cyclopropylcarbinol,4-methoxy-3-[2-(1-naphthyl)ethoxy]benzaldehyde (yield 54.1%) wasobtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ3.67 (2H, t, J=7.81 Hz), 3.96 (3H, s), 4.41(2H, t, J=7.81 Hz), 6.98 (1H, d, J=8.30 Hz), 7.37 (1H, d, J=1.47 Hz),7.41-7.46 (2H, m), 7.48 (1H, dd, J=7.82,0.97 Hz), 7.51 (1H, dd,J=3.42,1.47 Hz), 7.55 (1H, dd, J=6.84,1.47 Hz), 7.77 (1H, dd,J=6.84,2.45 Hz), 7.87 (1H, dd, J=8.30,0.97 Hz), 8.11 (1H, d, J=8.30 Hz),9.80 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-[2-(1-naphthyl)ethoxy]benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]propiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.23 (1H, broad s), 2.60-2.71 (2H, m),3.66 (2H,t, J=7.32 Hz),3.88 (3H, s), 4.36 (2H, t, J=7.32 Hz),4.88 (1H, t, J=6.35Hz), 6.84 (1H, d, J=1.95 Hz), 6.86 (1H, d, J=8.30 Hz),6.90 (1H, dd,J=8.30,1.95 Hz), 7.40-7.56 (4H, m),7.77 (1H, dd, J=7.33,1.96 Hz),7.88(1H, dd, J=8.79,1.47 Hz),8.12 (1H, d, J=8.30 Hz)

(3) Synthesis of6-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 61.4%) was obtained as a light yellowsolid.

¹-H-NMR (400 MHz, CDCl₃) δ1.93-2.03 (1H, m), 2.07-2.11 (1H, m), 3.32(1H, ddd, J=11.23,5.86,3.42 Hz), 3.40 (1H, ddd, J=11.23,11.23,4.88 Hz),3.66 (2H, t, J=7.81 Hz), 3.88 (3H, s), 4.34 (2H, t, J=7.81 Hz), 5.17(1H, dd, J=10.26,2.44 Hz), 5.84 (1H, broad s), 6.84 (1H, d, J=1.47 Hz),6.87 (1H, d, J=8.30 Hz), 6.89 (1H, dd, J=8.30,1.47 Hz), 7.38-7.56 (4H,m), 7.76 (1H, dd, J=7.32,1.95 Hz), 7.87 (1H, d, J=7.81 Hz), 8.11 (1H, d,J=8.30 Hz)

Example 68 Synthesis of6-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 68 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-[2-(1-naphthyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 67 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 77.8%) was obtained as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ2.01-2.15 (2H, m), 3.00 (3H, s), 3.20 (1H, ddd,J=11.72,5.86,2.93 Hz), 3.42 (1H, ddd, J=11.72,11.72,5.86 Hz), 3.66 (2H,t, J=7.32 Hz), 3.88 (3H, s), 4.35 (2H, m), 5.13 (1H, dd, J=9.77,3.42Hz), 6.84-6.87 (2H, m), 6.89 (1H, dd, J=8.30,1.47 Hz), 7.41-7.74 (4H,m), 7.76 (1H, dd, J=7.33,1.95 Hz), 7.86 (1H, d, J=7.81 Hz), 8.10 (1H, d,J=8.30 Hz)

Example 69 Synthesis of6-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 69 of Table 1) (1) Synthesis of3-(2-ethylbutoxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using 2-ethylbutanolinstead of cyclopropylcarbinol, 3-(2-ethylbutoxy)-4-methoxybenzaldehyde(yield 78.4%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ0.94 (6H, t, J=7.32 Hz), 1.43-1.56 (4H, m),1.80 (1H, m), 3.94 (3H, s), 3.94 (2H, d, J=6.35 Hz), 6.97 (1H, d, J=7.82Hz), 7.41 (1H, d, J=1.95 Hz), 7.44 (1H, dd, J=7.82,1.95 Hz), 9.85 (1H,s)

(2) Synthesis of3-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-(2-ethylbutoxy)-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3-hydroxypropiononitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.94 (6H, t, J=7.33 Hz), 1.42-1.56 (4H, m),1.77 (1H, m),2.74 (1H, dd, J=16.60,6.35 Hz), 2.79 (1H, dd, J=16.60,6.35Hz), 3.85 (3H, s), 3.89 (2H, d, J=6.35 Hz), 4.98 (1H, t, J=6.35 Hz),6.86 (1H, d, J=8.30 Hz), 6.91 (1H, dd, J=8.30,1.95 Hz), 6.95 (1H, d,J=1.95 Hz)

(3) Synthesis of6-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3-hydroxypropiononitrile insteadof 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 58.5%) was obtained as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ0.94 (6H, t, J=7.32 Hz), 1.40-1.57 (4H, m),1.77 (1H, m), 2.05-2.15 (1H, m), 2.17-2.21 (1H, m), 3,41 (1H, ddd,J=11.23, 5.86, 3.42 Hz), 3,49 (1H, ddd, J=11.23, 11.23, 5.37 Hz), 3.86(3H, s), 3.89 (2H, d, J=5.86 Hz), 5.26 (1H, dd, J=10.26, 2.93 Hz), 5.70(1H, broad s), 6.84-6.93 (3H, m)

Example 70 Synthesis of6-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 70 of Table 1)

According to the same procedure as in Example 8, using the6-[3-(2-ethylbutoxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 69 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 97.9%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.94 (6H, t, J=7.32 Hz), 1.42-1.55 (4H, m),1.76 (1H, m,J=6.35 Hz), 2.15-2.23 (2H, m), 3.04 (3H, s), 3.26 (1H, ddd,J=11.72, 5.37, 3.42 Hz), 3.48 (1H, ddd, J=11.72, 10.26, 6.35 Hz), 3.85(3H, s), 3.88 (2H, d, J=6.35 Hz), 5.21 (1H, dd, J=11.28, 3.42 Hz),6.85-6.92 (3H, m)

Example 71 Synthesis of3-ethyl-6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 71 of Table 1)

According to the same procedure as in Example 25, using ethyl iodideinstead of methyl iodide, the above-described compound (yield 92.0%) wasobtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.21 (3H, t, J=7.32 Hz), 2.13-2.26 (2H, m),3.23-3.32 (1H, m), 3.23 (2H, dm, J=16.60 Hz), 3.38 (2H, dd, J=16.60,6.35 Hz), 3.40-3,49 (1H, m), 3.43 (2H, q, J=7.32 Hz), 3.81 (3H, s),5.18-5.23 (2H, m), 6.86 (1H, d, J=8.30 Hz), 6.92 (1H, d, J=8.30 Hz),6.96 (1H, s), 7.16-7.23 (4H, m)

Example 72 Synthesis of6-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 72 of Table 1) (1) Synthesis of4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]benzaldehyde

According to the same procedure as in Example 4(1), using2-(4-methyl-5-thiazolyl)ethanol instead of cyclopropylcarbinol,4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]benzaldehyde (yield 79.9%)was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ2.46 (3H, s), 3.33 (2H, t, J=6.84 Hz), 3.96(3H, s), 4.24 (2H, t, J=6.84 Hz), 6.99 (1H, d, J=8.30 Hz), 7.39 (1H, d,J=1.95 Hz), 7.48 (1H, dd, J=8.30, 1.95 Hz), 8.60 (1H, s), 9.84 (1H, s)

(2) Synthesis of3-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3-hydroxypropiononitrilewas obtained as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ2.44 (3H, s), 2.60 (1H, d, J=3.42 Hz), 2.74(2H, m), 3.30 (2H, t, J=6.83 Hz), 3.87 (3H, s), 4.19 (2H, t, J=6.83 Hz),4.97 (1H, m), 6.88 (1H, d, J=7.81 Hz), 6.93-6.95 (2H, m), 8.57 (1H, s)

(3) Synthesis of6-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 27.3%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ2.07 (1H, dddd, J=14.16, 10.25, 10.25, 5.86Hz), 2.17-2.21 (1H, m), 2.45 (3H, s), 3.31 (2H, t, J=6.84 Hz), 3.37-3.42(1H, m), 3.48 (1H, ddd, J=11.27, 10.25, 4.88 Hz), 3.87 (3H, s), 4.19(2H, ddd, J=6.84, 6.84, 1.95 Hz), 5.25 (1H, dd, J=10.25, 2.44 Hz), 5.40(1H, broad s), 6.86-6.93 (3H, m), 8.60 (1H, s)

Example 73 Synthesis of6-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 70 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-[2-(4-methyl-5-thiazolyl)ethoxy]phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 72 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 54.8%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.08-2.22 (2H, m), 2.45 (3H, s), 3.03 (3H, s),3.25 (1H, ddd, J=11.71, 5.37, 2.93 Hz), 3.30 (2H, t, J=6.84 Hz), 3.48(1H, ddd, J=11.71, 11.23, 5.86 Hz), 3.87 (3H, s), 4.18 (2H, ddd, J=6.84,6.84, 2.93 Hz), 5.20 (1H, dd, J=9.76, 2.93 Hz), 6.85-6.91 (3H, m), 8.60(1H, s)

Example 74 Synthesis of6-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 74 of Table 1) (1) Synthesis of3-[2-(4-fluorophenyl)ethoxy]-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using4-fluorophenethyl alcohol instead of cyclopropylcarbinol,3-[2-(4-fluorophenyl)ethoxy]-4-methoxybenzaldehyde (yield 91.6%) wasobtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ3.15 (2H, t, J=7.32 Hz), 3.96 (3H, s), 4.25(2H, t, J=7.32 Hz), 6.98 (1H, d, J=8.30 Hz), 6.98-7.03 (2H, m),7.24-7.28 (2H, m), 7.39 (1H, d, J=1.47 Hz), 7.46 (1H, dd, J=8.30, 1.47Hz), 9.83 (1H, s)

(2) Synthesis of3-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-[2-(4-fluorophenyl)ethoxy]-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.31 (1H, broad s), 2.71 (1H, dd, J=16.60, 6.35Hz), 2.75 (1H, dd, J=16.60, 6.35 Hz), 3.13 (1H, d, J=7.33 Hz), 3.86 (3H,s), 4.20 (2H, t, J=7.33 Hz), 4.95 (1H, t, J=6.35 Hz), 6.87 (1H, d,J=8.79 Hz), 6.91-6.93 (2H, m), 6.98-7.02 (2H, m), 7.24-7.28 (2H, m)

(3) Synthesis of6-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 48.0%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ2.06 (1H, dddd, J=14.26, 10.25, 10.25, 5.86Hz), 2.14-2.21 (1H, m), 3.13 (2H, t, J=7.33 Hz), 3.36-3,40 (1H, m),3.44-3.82 (1H, m), 3.87 (3H, s), 4.19 (2H, ddd, J=7.33, 7.33, 2.44 Hz),5.25 (1H, dd, J=9.77, 2.44 Hz), 5.25 (1H, broad s), 6.85-6.90 (3H, m),7.00 (2H, m), 7.26 (2H, m)

Example 75 Synthesis of6-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 75 of Table 1)

According to the same procedure as in Example 8, using the6-[3-[2-(4-fluorophenyl)ethoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 74 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 57.3%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.07-2.21 (2H, m), 3.03 (3H, s), 3.13 (2H, t,J=7.33 Hz), 3.24 (1H, ddd, J=11.72, 5.86, 2.93 Hz), 3,47 (1H, ddd,J=11.72, 11.72, 5.86 Hz), 3.86 (3H, s), 4.19 (2H, ddd, J=7.33, 7.33,3.42 Hz), 5.19 (1H, dd, J=9.77, 3.42 Hz), 6.86-6.89 (3H, m), 6.98-7.02(2H, m), 7.24-7.27 (2H, m)

Example 76 Synthesis of6-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 76 of Table 1) (1) Synthesis of3-cyclopentylmethyloxy-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), usingcyclopentylcarbinol instead of cyclopropylcarbinol,3-cyclopentylmethyloxy-4-methoxybenzaldehyde (yield 80.6%) was obtainedas a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.36-1.42 (2H, m), 1.56-1.66 (4H, m), 1.83-1.92(2H, m), 2.46 (1H, m), 3.94 (2H, d, J=7.32 Hz), 3.95 (3H, s), 6.97 (1H,d, J=7.81 Hz), 7.41 (1H, d, J=1.95 Hz), 7.44 (1H, dd, J=7.81, 1.95 Hz),9.84 (1H, s)

(2) Synthesis of3-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-cyclopentylmethyloxy-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrile wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.36-1.42 (2H, m), 1.58-1.68 (4H, m), 1.83-1.91(2H, m), 2.30 (1H, d, J=2.93 Hz), 2.44 (1H, m, J=7.33 Hz), 2.76 (2H, m),3.86 (3H, s), 3.89 (2H, d, J=7.33 Hz), 4.98 (1H, m), 6.86 (1H, d, J=8.30Hz), 6.90 (1H, dd, J=8.30, 1.95 Hz), 6.95 (1H, d, J=1.95 Hz)

(3) Synthesis of6-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 22.6%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ1.34-1.39 (2H, m), 1.59-1.65 (4H, m), 1.82-1.90(2H, m), 2.10 (1H, dddd, J=14.16, 10.25, 10.25, 5.37 Hz), 2.17-2.23 (1H,m), 2.44 (1H, m, J=7.32 Hz), 3.38-3.43 (1H, m), 3,49 (1H, ddd, J=10.74,10.74, 4.88 Hz), 3.87 (3H, s), 3.88 (2H, d, J=7.32 Hz), 5.27 (1H, dd,J=10.25, 2.93 Hz), 5.28 (1H, broad s), 6.84-6.93 (3H, m)

Example 77 Synthesis of6-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 77 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopentylmethyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 76 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 84.3%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ1.35-1.39 (2H, m), 1.54-1.65 (4H, m), 2.13-2.22(2H, m), 2.43 (1H, m), 3.04 (3H, s), 3.26 (1H, ddd, J=11.72, 5.37, 3.42Hz), 3.48 (1H, ddd, J=11.72, 10.25, 5.37 Hz), 3.86 (3H, s), 3.88 (2H, d,J=6.83 Hz), 5.21 (1H, dd, J=9.28, 3.42 Hz), 6.83-6.88 (2H, m), 6.92 (1H,m)

Example 78 Synthesis of6-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 78 of Table 1) (1) Synthesis of4-methoxy-3-(trans-4-phenylcyclohexyloxy)benzaldehyde

According to the same procedure as in Example 4(1), usingcis-1-hydroxy-4-phenylcyclohexane instead of cyclopropylcarbinol,4-methoxy-3-(trans-4-phenylcyclohexyloxy)benzaldehyde (yield 37.5%) wasobtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ1.59-1.76 (4H, m), 2.01-2.04 (2H, m), 2.30-2.33(2H, m), 2.60 (1H, m), 3.96 (3H, s), 4.35-4.41 (1H, m), 7.00 (1H, d,J=7.81 Hz), 7.19-7.33 (5H, m), 7.46-7.48 (2H, m), 9.86 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(trans-4-phenylcyclohexyloxy)benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]propiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.56-1.74 (4H, m), 1.99-2.05 (2H, m), 2.27-2.32(2H, m), 2.58 (1H, m), 2.75 (1H, dd, J=16.60, 6.35 Hz), 2.79 (1H, dd,J=16.60, 6.35 Hz), 3.87 (3H, s), 4.24-4.29 (1H, m), 4.99 (1H, t, J=6.35Hz), 6.89 (1H, d, J=8.30 Hz), 6.96 (1H, dd, J=8.30, 1.95 Hz), 7.04 (1H,d, J=1.95 Hz), 7.18-7.32 (5H, m)

(3) Synthesis of6-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 59.6%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.62-1.73 (4H, m), 1.98-2.01 (2H, m), 2.06-2.16(1H, m), 2.19-2.22 (1H, m), 2.26-2.29 (2H, m), 2.58 (1H, m), 3.40 (1H,ddd, J=10.74, 5.86, 3.42 Hz), 3.50 (1H, ddd, J=10.74, 10.74, 5.37 Hz),3.88 (3H, s), 4.27 (1H, m), 5.27 (1H, dd, J=9.47, 2.45 Hz), 5.28 (1H,broad s), 6.89 (1H, d, J=8.30 Hz), 6.94 (1H, dd, J=8.30, 1.95 Hz), 7.00(1H, d, J=1.95 Hz), 7.18-7.32 (5H, m)

Example 79 Synthesis of6-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 79 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-(trans-4-phenylcyclohexyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 79 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 82.4%) was obtained as a pale yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.55-1.70 (4H, m), 1.98-2.01 (2H, m), 2.15-2.26(4H, m), 2.54-2.60 (1H, m), 3.04 (3H, s), 3.27 (1H, ddd, J=11.72, 5.37,3.42 Hz), 3.48 (1H, ddd, J=11.72, 10.25, 5.86 Hz), 3.87 (3H, s), 4.27(1H, m), 5.22 (1H, dd, J=9.28, 3.91 Hz), 6.87 (1H, d, J=8.30 Hz), 6.92(1H, dd, J=8.30, 1.96 Hz), 6.99 (1H, d, J=1.96 Hz), 7.18-7.32 (5H, m)

Example 80 Synthesis of6-[4-methoxy-3-(1-methylcyclopentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 80 of Table 1) (1) Synthesis of4-methoxy-3-(1-methylcyclopentyloxy)benzaldehyde

According to the same procedure as in Example 4(1), using1-methylcyclopentanol instead of cyclopropylcarbinol,4-methoxy-3-(1-methylcyclopentyloxy)benzaldehyde (yield 4.7%) wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.49 (3H, s), 1.61-1.73 (2H, m), 1.79-1.91 (2H,m), 2.12-2.18 (2H, m), 3.91 (3H, s), 6.98 (1H, d, J=8.30 Hz), 7.51 (1H,dd, J=8.30, 1.96 Hz), 7.51 (1H, d, J=1.96 Hz), 9.84 (1H, s)

(2) Synthesis of3-hydroxy-3-[4-methoxy-3-(1-methylcyclopentyloxy)phenyl]propiononitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(1-methylcyclopentyloxy)benzaldehyde instead of3,4-dimethoxybenzaldehyde,3-hydroxy-3-[4-methoxy-3-(1-methylcyclopentyloxy)phenyl]propiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.43 (3H, s), 1.59-1.73 (4H, m), 1.80-1.90 (2H,m), 2.03-2.15 (2H, m), 2.52 (1H, broad s), 2.71 (1H, dd, J=16.60, 6.35Hz), 2.76 (1H, dd, J=16.60, 6.35 Hz), 3.81 (3H, s), 4.94 (1H, t, J=6.35Hz), 6.86 (1H, d, J=8.30 Hz), 7.00 (1H, dd, J=8.30, 1.96 Hz), 7.02 (1H,d, J=1.96 Hz)

(3) Synthesis of6-[4-methoxy-3-(1-methylcyclopentyloxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-hydroxy-3-[4-methoxy-3-(1-methylcyclopentyloxy)phenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 13.2%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ1.42 (3H, s), 1.59-1.69 (4H, m), 1.85-1.89 (2H,m), 2.08-2.13 (4H, m), 3.39 (1H, ddd, J=11.23, 5.37, 3.42 Hz), 3.44-3.51(1H, m), 3.82 (3H, s), 5.25 (1H, dd, J=9.77, 2.93 Hz), 5.28 (1H, broad,s), 6.88 (1H, d, J=8.79 Hz), 6.99-7.02 (2H, m)

Example 81 Synthesis of6-[4-methoxy-3-(2-methylpropoxyphenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 81 of Table 1) (1) Synthesis of4-methoxy-3-(2-methylpropoxy)acetophenone

According to the same procedure as in Example 6(1), using the4-methoxy-3-(2-methylpropoxy)benzaldehyde produced in Example 65(1)instead of 3-cyclopentyloxy-4-methoxybenzaldehyde,4-methoxy-3-(2-methylpropoxy)acetophenone (yield 90.8%) was obtained asa yellow brown solid.

¹H-NMR (400 MHz, CDCl₃) δ1.06 (6H, d, J=6.84 Hz), 2.18 (1H, m), 2.56(3H, s), 3.82 (2H, d, J=6.84 Hz), 3.93 (3H, s), 6.88 (1H, d, J=8.30 Hz),7.51 (1H, d, J=1.96 Hz), 7.56 (1H, d, J=8.30, 1.96 Hz)

(2) Synthesis of3-[4-methoxy-3-(2-methylpropoxy)phenyl]-3-hydroxybutyronitrile

According to the same procedure as in Example 1(1), using4-methoxy-3-(2-methylpropoxy)acetophenone instead of3,4-dimethoxybenzaldehyde,3-[4-methoxy-3-(2-methylpropoxy)phenyl]-3-hydroxybutyronitrile wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.04 (6H, d, J=6.84 Hz), 1.76 (3H, s), 2.16(1H, m, J=6.84 Hz), 2.77 (1H, d, J=16.11 Hz), 2.83 (1H, d, J=16.11 Hz),3.78 (2H, d, J=6.84 Hz), 3.86 (3H, s), 6.85 (1H, d, J=8.30 Hz), 6.95(1H, dd, J=8.30, 2.45 Hz), 7.05 (1H, d, J=2.45 Hz)

(3) Synthesis of6-[4-methoxy-3-(2-methylpropoxy)phenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[4-methoxy-3-(2-methylpropoxy)phenyl]-3-hydroxybutyronitrile insteadof 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-describedcompound (yield 43.0%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ1.03 (6H, d, J=6.35 Hz), 1.66 (3H, s),2.10-2.18 (2H, m), 2.31 (1H, ddd, J=13.67, 4.40, 3.91 Hz), 3.07 (1H,ddd, J=11.23, 11.23, 4.40 Hz), 3.27 (1H, dddd, J=11.23, 5.37, 3.91, 3.91Hz), 3.76 (1H, dd, J=9.28, 6.35 Hz), 3.79 (1H, dd, J=9.28, 6.35 Hz),3.86 (3H, s), 5.02 (1H, broad s), 6.85-6.90 (3H, m)

Example 82 Synthesis of3,6-dimethyl-6-[4-methoxy-3-(2-methylpropoxy)phenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 82 of Table 1)

According to the same procedure as in Example 8, using the6-[4-methoxy-3-(2-methylpropoxy)phenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 82 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 79.7%) was obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.03 (6H, d, J=6.84 Hz), 1.62 (3H, s), 2.15(1H, m, J=6.84 Hz), 2.18 (1H, ddd, J=14.26, 10.74, 5.86 Hz), 2.35 (1H,ddd, J=14.26, 4.89, 3.42 Hz), 2.90 (3H, s), 3.03 (1H, ddd, J=11.72,10.74, 4.89 Hz), 3.13 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3.75 (1H, dd,J=9.28, 6.84 Hz), 3.78 (1H, dd, J=9.28, 6.84 Hz), 3.86 (3H, s), 6.82(1H, dd, J=8.30, 1.95 Hz), 6.85 (1H, d, J=8.30 Hz), 6.89 (1H, d, J=1.95Hz)

Example 83 Synthesis of 6-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-34,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound No. 83 of Table 1) (1)Synthesis of 3-(2-benzyloxyethoxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using2-benzyloxyethanol instead of cyclopropylcarbinol,3-(2-benzyloxyethoxy)-4-methoxybenzaldehyde (yield 83,4%) was obtainedas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ3.89 (2H, t, J=4.88 Hz), 3.95 (3H, s), 4.27(2H, t, J=4.88 Hz), 4.65 (2H, s), 6.97 (1H, d, J=8.30 Hz), 7.27-7.48(7H, m), 9.83 (1H, s)

(2) Synthesis of3-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-(2-benzyloxyethoxy)-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3-hydroxypropiononitrile wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ2.45 (1H, broad s), 2.65 (1H, dd, J=16.60, 6.34Hz), 2.70 (1H, dd, J=16.60, 6.34 Hz), 3.86 (3H, s), 3.87 (2H, t, J=4.88Hz), 4.22 (2H, t, J=4.88 Hz), 4.63 (2H, s), 4.91 (1H, t, J=6.34 Hz),6.85 (1H, d, J=8.30 Hz), 6.92 (1H, dd, J=8.30, 1.95 Hz), 6.98 (1H, d,J=1.95 Hz), 7.34-7.36 (5H, m)

(3) Synthesis of6-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 38.4%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.98-2.08 (1H, m), 2.13 (1H, dddd, J=16.61,8.30, 2.93, 2.93 Hz), 3.35 (1H, ddd, J=11.72, 5.86, 3.42 Hz), 3,41-3.48(1H, m), 3.87 (3H, s), 3.87 (2H, t, J=5.37 Hz), 4.24 (2H, t, J=5.37 Hz),4.64 (2H, s), 5.23 (1H, dd, J=10.25, 2.93 Hz), 5.46 (1H, broad s), 6.86(1H, d, J=8.30 Hz), 6.92 (1H, dd, J=8.30, 1.95 Hz), 6.96 (1H, d, J=1.95Hz), 7.27-7.40 (5H, m)

Example 84 Synthesis of6-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 84 of Table 1)

According to the same procedure as in Example 8, using the6-[3-(2-benzyloxyethoxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 84 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 87.9%) was obtained as a yellow brownoil.

¹H-NMR (400 MHz, CDCl₃) δ2.07-2.18 (2H, m), 3.03 (3H, s), 3.22 (1H, ddd,J=11.72, 5.86, 3.42 Hz), 3.44 (1H, ddd, J=11.72, 11.72, 5.86 Hz), 3.86(3H, s), 3.86 (2H, t, J=4.88 Hz), 4.23 (2H, t, J=4.88 Hz), 4.63 (2H, s),5.17 (1H, dd, J=9.76, 2.42 Hz), 6.85 (1H, d, J=8.30 Hz), 6.90 (1H, dd,J=8.30, 1.47 Hz), 6.95 (1H, d, J=1.47 Hz), 7.28-7.40 (5H, m)

Example 85 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-5,5-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 85 of Table 1) (1) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-2,2-dimethyl-3-hydroxypropiononitrile

According to the same procedure as in Example 2(1), usingisobutyronitrile instead of acetonitrile,3-(3-cyclopentyloxy-4-methoxyphenyl)-2,2-dimethyl-3-hydroxypropiononitrilewas obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ1.21 (3H, s), 1.46 (3H, s), 1.51-1.65 (2H, m),1.79-2.02 (6H, m), 3.85 (3H, s), 4.49 (1H, s), 4.80 (1H, m), 6.84 (1H,d, J=8.30 Hz), 6.90 (1H, dd, J=8.30, 1.95 Hz), 7.04 (1H, d, J=1.95 Hz)

(2) Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-5,5-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-(3-cyclopentyloxy-4-methoxyphenyl)-2,2-dimethyl-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 54.3%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ0.92 (3H, s), 0.95 (3H, s), 1.60-1.62 (2H, m),1.84-1.95 (6H, m), 3.04 (1H, dd, J=11.72, 3.91 Hz), 3.22 (1H, d, J=11.72Hz), 3.84 (3H, s), 4.79 (1H, m), 4.97 (1H, s), 6.79-6.85 (3H, m), 6.95(1H, broad)

Example 86 Synthesis of6-(3-cyclopentyloxy-4-methoxyphenyl)-3,5,5-trimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 86 of Table 1)

According to the same procedure as in Example 8, using the6-(3-cyclopentyloxy-4-methoxyphenyl)-5,5-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 85 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 63.7%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ0.92 (3H, s), 0.95 (3H, s), 1.58-1.62 (2H, m),1.82-1.98 (6H, m), 2.92 (1H, d, J=11.72 Hz), 3.04 (3H, s), 3.29 (1H, d,J=11.72 Hz), 3.84 (3H, s), 4.79 (1H, m), 4.95 (1H, s), 6.75-6.85 (3H, m)

Example 87 Synthesis of5.5-dimethyl-6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 87 of Table 1) (1) Synthesis of2,2-dimethyl-3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile

According to the same procedure as in Example 24(2), usingisobutyronitrile instead of acetonitrile,2,2-dimethyl-3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.24 (3H, s), 1.47 (3H, s), 2.24 (1H, broad s),3.20-3.27 (2H, m), 3.36-3,45 (2H, m), 3.82 (3H, s), 4.48 (1H, s), 5.22(1H, m), 6.86 (1H, d, J=8.30 Hz), 6.96 (1H, dd, J=8.30, 1.95 Hz), 7.11(1H, d, J=1.95 Hz), 7.16-7.19 (2H, m), 7.22-7.24 (2H, m)

(2) Synthesis of5,5-dimethyl-6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using2,2-dimethyl-3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 75.9%) was obtained as an off whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ0.96 (3H, s), 1.00 (3H, s), 3.06 (1H, dd,J=11.72, 4.39 Hz), 3.21-3.29 (3H, m), 3.36 (2H, ddd, J=16.60, 5.86, 5.86Hz), 3.82 (3H, s), 5.00 (1H, s), 5.22 (1H, m), 5.25 (1H, broad),6.86-6.90 (3H, m), 7.16-7.19 (2H, m), 7.22-7.28 (2H, m)

Example 88 Synthesis of6-[3-(2-indanyloxy)-4-methoxyphenyl]-3,5,5-trimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 88 of Table 1)

According to the same procedure as in Example 8, using the5,5-dimethyl-6-[3-(2-indanyloxy)-4-methoxyphenyl]-5,5-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-oneproduced in Example 87 instead of6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, theabove-described compound (yield 86.2%) was obtained as an off whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ0.94 (3H, s), 0.98 (3H, s), 2.93 (1H, d,J=11.72 Hz), 3.05 (3H, s), 3.22 (2H, ddd, J=16.60, 6.84, 3.91 Hz), 3.30(1H, d, J=11.72 Hz), 3.35 (2H, ddd, J=16.60, 6.84, 6.84 Hz), 3.82 (3H,s), 4.96 (1H, s), 5.20 (1H, m), 6.85 (2H, s), 6.88 (1H, s), 7.16-7.18(2H, m), 7.22-7.24 (2H, m)

Example 89 Synthesis of6-[3-(1-benzyl-4-piperidyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 89 of Table 1) (1) Synthesis of3-(1-benzyl-4-piperidyloxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using1-benzyl-4-hydroxypiperidine instead of cyclopropylcarbinol,3-(1-benzyl-4-piperidyloxy)-4-methoxybenzaldehyde (yield 64.4%) wasobtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ1.73-1.92 (2H, m), 2.00-2.06 (2H, m), 2.25-2.30(2H, m), 2.78-2.84 (2H, m), 3.54 (2H, s), 3.93 (3H, s), 4.38 (1H, m),6.98 (1H, d, J=8.30 Hz), 7.32 (1H, d, J=1.46 Hz), 7.33 (5H, m), 7.44(1H, dd, J=8.30, 1.46 Hz), 9.83 (1H, s)

(2) Synthesis of3-[3-(1-benzyl-4-piperidyloxy)-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-(1-benzyl-4-piperidyloxy)-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-(1-benzyl-4-piperidyloxy)-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ1.84-1.88 (2H, m), 1.96 (2H, m), 2.25 (2H, m),2.72-2.78 (5H, m), 3.53 (2H, s), 3.84 (3H, s), 4.27 (1H, m), 4.95 (1H,t, J=6.35 Hz), 6.87 (1H, d, J=8.30 Hz), 6.94 (1H, dd, J=8.30, 1.95 Hz),6.98 (1H, d, J=1.95 Hz), 7.31-7.32 (5H, m)

(3) Synthesis of6-[3-(1-benzyl-4-piperidyloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-(1-benzyl-4-piperidyloxy)-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 41.0%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.85-1.89 (2H, m), 1.97 (2H, m), 2.07 (1H,dddd, J=13.67, 10.25, 10.25, 5.86 Hz), 2.17-2.20 (1H, m), 2.25 (2H, m),2.79 (2H, m), 3.36-3,41 (1H, m), 3.44-3.48 (1H, m), 3.54 (2H, s), 3.84(3H, s), 4.27 (1H, m), 5.23 (1H, broad s), 5.25 (1H, dd, J=9.76, 2.93Hz), 6.87 (1H, d, J=8.30 Hz), 6.92-6.94 (2H, m), 7.30-7.33 (4H, m)

Example 90 Synthesis of6-[3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 90 of Table 1) (1) Synthesis of3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using2-(cyclopropylmethyloxy)ethanol instead of cyclopropylcarbinol,3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxybenzaldehyde (yield 87.2%)was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ0.21-0.24 (2H, m), 0.52-0.57 (2H, m), 1.10 (1H,m), 3.40 (2H, d, J=6.84 Hz), 3.89 (2H, t, J=4.88 Hz), 3.95 (3H, s), 4.25(2H, t, J=4.88 Hz), 6.98 (1H, d, J=7.81 Hz), 7.45-7.48 (2H, m), 9.84(1H, s)

(2) Synthesis of3-[3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a dark brown oil.

¹H-NMR (400 MHz, CDCl₃) δ0.20-0.24 (2H, m), 0.52-0.56 (2H, m), 1.09 (1H,m), 2.41 (1H, broad), 2.73 (1H, dd, J=16.60, 6.35 Hz), 2.77 (1H, dd,J=16.60, 6.35 Hz), 3.39 (2H, d, J=6.83 Hz), 3.86 (3H, s), 3.86 (2H, t,J=5.37 Hz), 4.20 (2H, t, J=5.37 Hz), 4.97 (1H, t, J=6.35 Hz), 6.86 (1H,d, J=8.30 Hz), 6.94 (1H, dd, J=8.30, 1.95 Hz), 7.01 (1H, d, J=1.95 Hz)

(3) Synthesis of6-[3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-[2-(cyclopropylmethyloxy)ethoxy]-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 13,4%) was obtained as a pale brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ0.21-0.24 (2H, m), 0.52-0.56 (2H, m), 1.04-1.13(1H, m), 2.07 (1H, dddd, J=14.16, 10.25, 10.25, 5.86 Hz), 2.18-2.20 (1H,m), 3.36-3.42 (1H, m), 3.40 (2H, d, J=6.84 Hz), 3.48 (1H, ddd, J=11.23,11.23, 4.88 Hz), 3.86 (3H, s), 3.86 (2H, t, J=5.37 Hz), 4.20 (2H, t,J=5.37 Hz), 5.26 (1H, dd, J=10.25, 2.93 Hz), 5.35 (1H, broad), 6.86 (1H,d, J=8.30 Hz), 6.92 (1H, dd, J=8.30, 1.95 Hz), 6.97 (1H, d, J=1.95 Hz)

Example 91 Synthesis ofrel-(5R,6S)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 91 of Table 1, wherein the planar structural formula isshown) (1) Synthesis of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-2-phenylpropiononitrile

According to the same procedure as in Example 2(1), usingphenylacetonitrile instead of acetonitrile, a crude product of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-2-phenylpropiononitrile1.53 g was obtained as a yellow oil.

(2) Synthesis of3-amino-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-1-propanol

According to the same procedure as in Example 1(2), using3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-2-phenylpropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 51.3%) was obtained as a light yellowoil.

(3) Synthesis of1-(3-cyclopentyloxy-4-methoxyphenyl)-3-(methoxycarbonylamino)-2-phenyl-1-propanol

According to the same procedure as in Example 1(3), using3-amino-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-1-propanol insteadof 3-amino-1-(3,4-dimethoxyphenyl)-1-propanol, a diastereo mixture ofthe above-described compound was obtained as a colorless oil. Themixture was separated by flash column chromatography (SiO₂; eluted by1.5% methanol/methylene chloride) to obtain a large Rf value fraction0.36 g (yield 39.0%) and a small Rf value fraction 0.49 g (yield 53.5%).

(4) Synthesis ofrel-(5R,6S)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(3), using the large Rfvalue fraction of the1-(3-cyclopentyloxy-4-methoxyphenyl)-3-(methoxycarbonylamino)-2-phenyl-1-propanolobtained in (3) instead of1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol, theabove-described compound (yield 85.1%) was obtained as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ1.50-1.73 (8H, m), 3.50-3.53 (1H, m), 3.64-3.70(1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 4.38 (1H, m), 5.57 (1H,broad), 5.61 (1H, d, J=3,41 Hz), 6.27 (1H, d, J=1.95 Hz), 6.58 (1H, dd,J=8.30,1.95 Hz), 6.73 (1H, d, J=8.30 Hz), 6.91-6.93 (2H, m), 7.21-7.22(3H, m),

Example 92 Synthesis ofrel-(5R,6R)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 92 of Table 1, wherein the planar structural formula isshown)

According to the same procedure as in Example 1(3), using the small Rfvalue fraction of the1-(3-cyclopentyloxy-4-methoxyphenyl)-3-(methoxycarbonylamino)-2-phenyl-1-propanolobtained in Example 92(3) instead of1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol, theabove-described compound (yield 99.3%) was obtained as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ1.51-1.86 (8H, m), 3.24 (1H, ddd,J=10.74,10.25,5.37 Hz), 3.57 (1H, ddd, J=10.74,5.37,5.37 Hz), 3.69 (1H,m), 3.76 (3H, s), 4.58 (1H, m), 5.31 (1H, d, J=10.25 Hz), 5.70 (1H,broad), 6.59 (1H, s), 6.68 (2H, s), 7.02-7.04 (2H, m), 7.17-7.25 (3H, m)

Example 93 Synthesis of6-[3-(3-tetrahydrofuryloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 93 of Table 1) (1) Synthesis of3-(3-tetrahydrofuryloxy)-4-methoxybenzaldehyde

According to the same procedure as in Example 4(1), using3-hydroxytetrahydrofuran instead of cyclopropylcarbinol,3-(3-tetrahydrofuryloxy)-4-methoxybenzaldehyde (yield 71.3%) wasobtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ2.18-2.30 (2H, m), 3.89-3.93 (2H, m), 3.94 (3H,s), 3.99-4.07 (2H, m), 5.01-5.05 (1H, m), 6.99 (1H, d, J=8.30 Hz), 7.35(1H, d, J=1.95 Hz), 7.49 (1H, dd, J=8.30,1.95 Hz), 9.84 (1H, s)

(2) Synthesis of3-[3-(3-tetrahydrofuryloxy)-4-methoxyphenyl]-3-hydroxypropiononitrile

According to the same procedure as in Example 1(1), using3-(3-tetrahydrofuryloxy)-4-methoxybenzaldehyde instead of3,4-dimethoxybenzaldehyde,3-[3-(3-tetrahydrofuryloxy)-4-methoxyphenyl]-3-hydroxypropiononitrilewas obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ2.17-2.20 (2H, m), 2.74 (2H, d, J=6.35 Hz),3.85 (3H, s), 3.87-4.03 (4H, m), 4.97-4.98 (3H, m), 6.87-6.98 (3H, m)

(3) Synthesis of6-[3-(3-tetrahydrofuryloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one

According to the same procedure as in Example 1(2) to (3), using3-[3-(3-tetrahydrofuryloxy)-4-methoxyphenyl]-3-hydroxypropiononitrileinstead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, theabove-described compound (yield 24.7%) was obtained as a light brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ2.03-2.15 (2H, m), 2.16-2.23 (2H, m), 3.39 (1H,m), 3,49 (1H, m), 3.86 (3H, s), 3.87-4.06 (4H, m), 4.96-5.00 (1H, m),5.25-5.28 (1H, broad), 5.26 (1H, m), 6.88 (1H, m), 6.88 (1H, m), 6.94(1H, m)

TABLE 1

Compound No. R₁ R₂ R₃ R₄ R₅ R₆  1 Me Me H H H H  2

Me H H H H  3 Bu Me H H H H  4

Me H H H H  5 Me Me H Me H H  6

Me H Me H H  7

Me H Ph H H  8 Me Me Me H H H  9 Me Me

H H H 10

Me Me H H H 11

Me

H H H 12

Me

H H H 13

Me

H H H 14

Me

H H H 15

Me

H H H 16

Me

H H H 17

Me Bu H H H 18

Me

H H H 19

Me

H H H 20

Me

H H H 21

Me Me Me H H 22

Me

Me H H 23

Me H H H H 24

Me H H H H 25

Me Me H H H 26

Me H Et H H 27 Me Me H

H H 28

Me Et H H H 29

Me H

H H 30

Me H Bu H H 31

Me H

H H 32

Me

H H H 33

Me

H H H 34

Me

H H H 35

Me

H H H 36

Me H

H H 37

Me

H H H 38

Me

H H H 39

Me H

H H 40

Me H Me H H 41

Me H H H H 42

Me Me H H H 43

Me Me Me H H 44

Me Me H H H 45

Me H Me H H 46

Me H Me H H 47

Me Me Me H H 48

Me Me Me H H 49

Me Me H H H 50

Me H Me H H 51

Me Me Me H H 52 Bu Me H Me H H 53 Bu Me Me H H H 54 Bu Me Me Me H H 55

Me H H H H 56

Me H H H H 57

Me Me H H H 58

Me H H H H 59

Me Me H H H 60

Me H H H H 61

Me H H H H 62

Me Me H H H 63

Me H H H H 64

Me Me H H H 65

Me H H H H 66

Me Me H H H 67

Me H H H H 68

Me Me H H H 69

Me H H H H 70

Me Me H H H 71

Me Et H H H 72

Me H H H H 73

Me Me H H H 74

Me H H H H 75

Me Me H H H 76

Me H H H H 77

Me Me H H H 78

Me H H H H 79

Me Me H H H 80

Me H H H H 81

Me H Me H H 82

Me Me Me H H 83

Me H H H H 84

Me Me H H H 85

Me H H Me Me 86

Me Me H Me Me 87

Me H H Me Me 88

Me Me H Me Me 89

Me H H H H 90

Me H H H H 91

Me H H Ph H 92

Me H H H Ph 93

Me H H H H

Example 95 Production of Tablets

6-(3-Cyclopentyloxy-4-methoxyphenyl)-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 6 of Table 1) (30 g), lactose (253 g), corn starch (63 g),low substituted hydroxypropylcellulose (40 g), and calcium stearate (4g) were mixed together, then compressed by an ordinary method so thateach tablet contained 10 mg of the above compound.

Example 96 Production of Capsules

6-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(4-pyridylmethyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 12 of Table 1) (30 g), lactose (260 g), corn starch (66g), and calcium stearate (4 g) were mixed together, then were filledinto a gelatin capsule by an ordinary method so that each capsulecontained 10 mg of the above compound.

Example 97 Production of Inhalant

6-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one(Compound No. 10 of Table 1) (0.15 g) pulverized well to a particle sizeof 1 to 5 μm and lactose (60 g) (325 mesh, DMV Co.) were mixed together.This was filled in capsules by an ordinary method so that each capsulecontained (50 μg) of the compound. Inhalation was performed by charginga capsule in a powder inhalation container.

Test Example 1 Separation of Phosphodiesterase (PDE) and Measurement ofPDE Inhibitory Activity

Type I, III, IV, and V PDE isozymes were prepared to study the PDEinhibitory activities and selectivities with the compound of theinvention [Trends Pharmacol. Sci., 12, 19-27 (1992)]. Type I PDE waspurchased from Sigma Corp. Type III, IV, and V PDE isozymes werepartially purified from rats platelets (Type III and V) or neutrophils(Type IV). Each enzyme source was homogenized in a buffer (pH 6.5)containing 20 mM bisTris, 2 mM EDTA (ethylenediamine tetraacetate), 0.1mM PMSF (phenylmethylsulfonyl fluoride), 5 mM 2-mercaptoethanol, 0.001mM pepstatin, and 0.01 mM leupeptin and was centrifuged at 30,000×G for30 minutes to obtain a supernatant, which was applied to an ion exchangecolumn (Q-sepharose First Flow, Pharmacia Corp.) and was eluted with 0to 1M sodium acetate. Partially purified isozymes were identified byobserving the effects of conventional inhibitors.

Each PDE isozyme and the test compound dissolved in DMSO (dimethylsulfoxide) were added to 50 mM Tris-HCl buffer containing 5 mM magnesiumchloride. ³H-cAMP (for type III and IV PDE) or ³H-cGMP (for type I and VPDE) were added as substrates and were reacted at 30° C. for 30 minutes.The reaction was terminated by placing the test tube in boiling water of100° C. for 5 minutes. The nucleotides formed by PDE were broken down by5′-nucleotidase to ³H-adenosine or ³H-guanosine. The unreacted substrateand reaction product were separated through an ion-exchange column (QAEsephadex, Pharmacia Corp.) The eluted ³H-nucleoside was measured for itsradioactivity by a liquid scintillation counter. The inhibitingactivities of the compound of the present invention are shown by theIC₅₀ value (M). The inhibitory activities against Type IV is shown inTable 2. Further, the inhibitory activities of the test samples againstType I, III, and V are {fraction (1/10)} or less than that against typeIV.

TABLE 2 Type IV PDE inhibitory activity IC₅₀ Compound No. (M)  1 1.0 ×10⁻⁵  2 1.2 × 10⁻⁶  3 6.8 × 10⁻⁶  4 3.2 × 10⁻⁶  5 6.8 × 10⁻⁶  6 1.1 ×10⁻⁶  7 4.3 × 10⁻⁶  8 1.9 × 10⁻⁵  9 2.2 × 10⁻⁵ 10 1.3 × 10⁻⁶ 11 1.4 ×10⁻⁶ 12 7.3 × 10⁻⁸ 13 1.7 × 10⁻⁶ 14 6.1 × 10⁻⁶ 15 9.8 × 10⁻⁷ 16 5.5 ×10⁻⁶ 17 2.1 × 10⁻⁶ 18 4.1 × 10⁻⁷ 19 1.8 × 10⁻⁶ 20 3.5 × 10⁻⁶ 21 6.6 ×10⁻⁷ 22 5.9 × 10⁻⁶ 23 1.5 × 10⁻⁶ 24 1.3 × 10⁻⁷ 25 1.9 × 10⁻⁷ 26 3.5 ×10⁻⁶ 27 2.1 × 10⁻⁵ 28 1.7 × 10⁻⁶ 29 3.4 × 10⁻⁶ 30 9.0 × 10⁻⁶ 31 4.6 ×10⁻⁶ 32 3.2 × 10⁻⁵ 33 8.8 × 10⁻⁶ 34 8.6 × 10⁻⁷ 35 2.0 × 10⁻⁶ 36 1.6 ×10⁻⁶ 37 4.5 × 10⁻⁶ 38 2.2 × 10⁻⁶ 39 1.8 × 10⁻⁵ 40 5.0 × 10⁻⁸ 41 7.3 ×10⁻⁷ 42 1.0 × 10⁻⁶ 43 6.6 × 10⁻⁸ 44 1.5 × 10⁻⁶ 45 2.6 × 10⁻⁷ 46 4.9 ×10⁻⁷ 47 2.2 × 10⁻⁷ 48 7.0 × 10⁻⁷ 49 2.0 × 10⁻⁶ 50 1.1 × 10⁻⁶ 51 1.9 ×10⁻⁶ 52 1.4 × 10⁻⁶ 53 9.1 × 10⁻⁶ 54 2.0 × 10⁻⁶ 55 1.7 × 10⁻⁶ 56 9.4 ×10⁻⁷ 57 1.3 × 10⁻⁶ 58 9.4 × 10⁻⁶ 59 2.7 × 10⁻⁵ 60 5.2 × 10⁻⁵ 61 3.2 ×10⁻⁶ 62 3.3 × 10⁻⁶ 63 3.4 × 10⁻⁶ 64 4.6 × 10⁻⁶ 65 2.2 × 10⁻⁶ 66 3.8 ×10⁻⁶ 67 1.1 × 10⁻⁶ 68 2.6 × 10⁻⁶ 69 5.0 × 10⁻⁶ 70 3.5 × 10⁻⁶ 71 3.1 ×10⁻⁷ 72 8.3 × 10⁻⁶ 73 7.3 × 10⁻⁶ 74 1.3 × 10⁻⁶ 75 1.8 × 10⁻⁶ 76 2.9 ×10⁻⁶ 77 3.3 × 10⁻⁶ 78 1.9 × 10⁻⁶ 79 1.2 × 10⁻⁶ 80 1.5 × 10⁻⁶ 81 1.3 ×10⁻⁶ 82 1.9 × 10⁻⁶ 83 3.4 × 10⁻⁶ 84 3.1 × 10⁻⁶ 85 7.8 × 10⁻⁷ 86 8.6 ×10⁻⁷ 87 8.8 × 10⁻⁸ 88 1.9 × 10⁻⁷ 89 3.5 × 10⁻⁵ 90 1.9 × 10⁻⁶ 91 2.7 ×10⁻⁶ 92 9.0 × 10⁻⁷ 93 3.7 × 10⁻⁶

Test Example 2 Inhibitory effects on activity of rat neutrophils

The release of super oxide anions was measured so as to study theinhibitory effects of the compound on inflammatory leukocytes, that is,neutrophils.

Blood sample was obtained from Wister rats anesthetized with ether. Itwas superposed on a blood cell separation solution (Polymorphoprep1.113, made by Naicomet Co. (phonetic)) and the neutrophils wereseparated by centrifugation. The neutrophils were resuspended in aHank's balanced salt solution at a concentration of 0.5×10⁴ cell/ml. 0.1mM of Lusigenin and the test substance dissolved in DMSO were added to 2ml of the cell-suspension. The chemiluminescence generated bystimulation of 0.3 μM calcium ionophore A23187 was measured by achemiluminescence reader so as to evaluate the release of super oxideanions. The efficacy of the compounds of the present invention wasexpressed by an IC₅₀ value and is shown in Table 3.

TABLE 3 Inhibitory action of super oxide anion release from ratneutrophils Compound No. IC₅₀ (M) 1 8.8 × 10⁻⁶ 2 5.5 × 10⁻⁷ 5 2.4 × 10⁻⁶8 4.1 × 10⁻⁶ 9 2.3 × 10⁻⁶ 10  9.0 × 10⁻⁸ 11  5.0 × 10⁻⁸

Test Example 3 Inhibitory effect on antigen-induced Bronchospasm(anti-asthmatic action)

A Hartley male guinea pig was sensitized by intramuscular administrationof 35 mg Ovalbumin (OA) on first day and fourth day, and used after 24thday. A trachial canula was introduced in the guinea pig anesthetizedwith pentobarbital and artificial ventilation was performed 25 to 29days after the first sensitization. The overflow of the ventilation wasmeasured by the Konzett-Roessler method while 0.2 mg/kg OA wereadministered intravenously. The test compound was dissolved inpolyethylene glycol 400 and intravenously administered 10 minutes beforeadministration of the antigens. The effect of the present invention wasexpressed by the ED₅₀ value and is shown in Table 4.

TABLE 4 Action for suppressing antigen- Compound No. inducedbronchospasms ED₅₀ (mg/kg)  2 0.23  4 0.23  5 0.30  6 0.30 10 0.95 113.1 14 2.4 16 2.1 20 8.5 21 0.29 23 13.6 24 1.6 25 0.061 26 2.4 28 7.440 0.47 43 0.29 46 11.4 49 3.10 50 0.30 51 2.23 56 1.72 57 15.9 61 1.8465 0.22 66 0.051 71 2.67 76 0.27 81 0.028 82 0.045

Test Example 4 Acute Toxicity Test

Compounds No. 1 to 93 were suspended in a saline containing 0.5% sodiumcarboxylmethylcellulose and were administered intraperitoneally. Thesurvival rate of the next day was examined. No death was observed at adosage of 30 mg/kg of any compound.

Industrial Applicability

As described above, the compound according to the present inventionexhibits an excellent type IV PDE inhibitory activity and is very usefulfor treating inflammatory diseases such as asthma and dermatitis andautoimmune diseases such as multiple sclerosis and rheumatism.

What is claimed is:
 1. A 6-phenyltetrahydro-1,3-oxazin-2-one derivativehaving the formula (I):

wherein: R₁ represents an unsubstituted or substituted C₁ to C₈ alkylgroup, an unsubstituted or substituted C₃ to C₇ cycloalkyl group, anunsubstituted or substituted heterocycle, or a polycyclic hydrocarbon;R₂ represents a C₁ to C₄ alkyl group; R₃ is a hydrogen atom, anunsubstituted or substituted C₁ to C₅ alkyl group, an unsubstituted orsubstituted C₃ to C₇ cycloalkyl group, an unsubstituted or substitutedaryl group, an unsubstituted or substituted heteroaryl group, or an acylgroup; R₄ is a hydrogen atom, an unsubstituted or substituted C₁ to C₆alkyl group, an unsubstituted or substituted aryl group, or anunsubstituted or substituted heteroaryl group; and R₅ and R₆ are eachindependently a hydrogen atom, an unsubstituted or substituted C₁ to C₅alkyl group, an unsubstituted or substituted C₃ to C₇ cycloalkyl group,an unsubstituted or substituted aryl group, or an unsubstituted orsubstituted heteroaryl group; an optical isomer or a pharmacologicallyacceptable salt thereof, a hydrate thereof or a solvate thereof with asolvent selected from the group consisting of methanol, ethanol,isopropanol, butanol, acetone, ethyl acetate and chloroform.
 2. Acompound as claimed in claim 1, wherein R₁ represents a C₁ to C₆ alkylgroup; a C₁ to C₅ alkyl group substituted with at least one groupselected from the group consisting of an unsubstituted or substitutedaryl group, an unsubstituted or substituted heterocyclic ring group, anunsubstituted or substituted alkoxy group, and an unsubstituted orsubstituted C₃ to C₆ cycloalkyl group; a cyclopentyl group; abenzylpiperidyl group; a tetrahydrofuryl group; a dibenzocycloheptylgroup; or an indanyl group.
 3. A compound as claimed in claim 1, whereinR₁ represents a methyl group; a butyl group; a 2-methylpropyl group; a2-ethylbutyl group; a C₁ to C₅ alkyl group substituted with a phenylgroup, a pyridyl group, a naphthyl group, a methylthiazonyl group, afluorophenyl group, a benzylpiperazinyl group, a benzylpiperidyl group,a benzyloxy group, a cyclopropylmethoxy group, or a C₃ to C₆ cycloalkylgroup which may have a phenyl group; a cyclopentyl group; abenzylpiperidyl group; tetrahydrofuryl group; a dibenzocycloheptylgroup; or a 2-indanyl group.
 4. A compound as claimed in claim 1 or 2,wherein R₂ represents a methyl group.
 5. A compound as claimed in claim1, wherein R₃ represents a hydrogen atom; a C₁ to C₄ alkyl group; anaryl group which may be substituted with a halogen atom; a heteroarylgroup; a C₁ to C₃ alkyl group substituted with a C₄ to C₆ cycloalkylgroup containing at least one hetero atom selected from the groupconsisting of oxygen, nitrogen, and sulfur atoms; anethyoxycarbonylmethyl group; or a benzoyl group.
 6. A compound asclaimed in claim 1, wherein R₄ represents a hydrogen atom, a C₁ to C₄alkyl group, a phenyl group, a thiazolyl group, a thienyl group, or apyridyl group.
 7. A compound as claimed in claim 1, wherein R₅ and R₆each independently represent a hydrogen atom, a methyl group, or aphenyl group.
 8. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmacologically acceptable carrier.
 9. A6-phenyltetrahydro-1,3-oxazin-2-one derivative having the formula (I):

wherein: R₁ represents a C₁ to C₈ alkyl group which may be substitutedwith one substituent, a C₃ to C₇ cycloalkyl group which may besubstituted with one substituent, a 5- or 6-membered heterocyclic groupcontaining at least one heteroatom selected from the group consisting ofoxygen, nitrogen and sulfur atoms which may be substituted with onesubstituent, or a C₉ to C₁₅ bicyclic or tricyclic hydrocarbon; R₂represents a C₁ to C₄ alkyl group; R₃ represents a hydrogen atom, a C₁to C₅ alkyl group which may be substituted with one substituent, a C₃ toC₇ cycloalkyl group which may be substituted with one substituent, a C₆to C₁₀ monocyclic or bicyclic aromatic group which may be substitutedwith one substituent, a 5- or 6-membered heteroaryl group containing atleast one hetero atom selected from oxygen, nitrogen, and sulfur atomswhich may be substituted with one substituent, or an acyl group; R₄represents a hydrogen atom, a C₁ to C₆ alkyl group which may besubstituted with one substituent, a C₆ to C₁₀ monocyclic or bicyclicaromatic group which may be substituted with one substituent, or a 5- or6-membered heteroaryl group containing at least one hetero atom selectedfrom oxygen, nitrogen, and sulfur atoms which may be substituted withone substituent; and R₅ and R₆ each independently represent a hydrogenatom, a C₁ to C₅ alkyl group which may be substituted with onesubstituent, a C₃ to C₇ cycloalkyl group which may be substituted withone substituent, a C₆ to C₁₀ monocyclic or bicyclic aromatic group whichmay be substituted with one substituent, or a 5- or 6-memberedheteroaryl group containing at least one hetero atom selected fromoxygen, nitrogen, and sulfur atoms which may be substituted with onesubstituent; an optical isomer or a pharmacologically acceptable saltthereof, a hydrate thereof or a solvate thereof with a solvent selectedfrom the group consisting of methanol, ethanol, isopropanol, butanol,acetone, ethyl acetate and chloroform.
 10. A compound as claimed inclaim 9, wherein R₁ represents a C₁ to C₆ alkyl group, a cyclopentylgroup, a benylpiperidyl group, a tetrahydrofuryl group, adibenzocycloheptyl group an indanyl group, a C₁ to C₅ alkyl groupsubstituted with at least one group selected from the group consistingof 5 to 10 membered monocyclic and bicyclic heterocyclic groupscontaining at least one hetero atom selected from the group consistingof oxygen, nitrogen, and sulfur atoms which may be substituted with onesubstituent, an alkoxy group which may be substituted with onesubstituent, a C₃ to C₆ cycloalkyl group which may be substituted withone substituent, and a C₆ to C₁₀ monocyclic or bicyclic aromatic groupwhich may be substituted with one substituent.
 11. A compound as claimedin claim 9, wherein R₁ represents a methyl group, a butyl group, a2-methyl-propyl group, a 2-ethyl butyl group, a cyclopentyl group, abenzylpiperidyl group, a tetrahydrofuryl group, a dibenzylcycloheptylgroup, a 2-indanyl group, or a C₁ to C₅ alkyl group substituted with aphenyl group, a pyridyl group, a naphthyl group, a methylthiazolylgroup, a fluorophenyl group, a benzylpiperazinyl group, a benzylpiperylgroup, a benzyloxy group, a cyclopropylmethoxy group, or a C₃ to C₆cycloalkyl group which may have a phenyl group.
 12. A compound asclaimed in claim 9, wherein R₂ represents a methyl group.
 13. A compoundas claimed in claim 9, wherein R₃ represents a hydrogen atom; a C₁ to C₄alkyl group; an ethyoxycarbonylmethyl group; a benzoyl group; or a C₁ toC₃ alkyl group, substituted with one group selected from the groupconsisting of (1) a C₆ to C₁₀ monocyclic or bicyclic aromatic groupwhich may be substituted with one substituent, (2) a 5 to 10 memberedmonocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfuratoms which may be substituted with one substituent, and (3) a C₄ to C₆cycloalkyl group containing at least one hetero atom selected from thegroup consisting of oxygen, nitrogen, and sulfur atoms.
 14. A compoundas claimed in claim 9, wherein R₄ represents a hydrogen atom, a C₁ to C₄alkyl group, a phenyl group, a thiazolyl group, a thienyl group, or apyridyl group.
 15. A compound as claimed in claim 9, wherein R₅ and R₆each independently represent a hydrogen atom, a methyl group, or aphenyl group.
 16. A pharmaceutical composition comprising a compoundaccording to claim 9 and a pharmacologically acceptable carrier.
 17. Amethod for treating dermatitis in a patient comprising administering atherapeutically effective amount of a pharmaceutical compositionaccording to claim
 8. 18. A method for treating dermatitis in a patientcomprising administering a therapeutically effective amount of apharmaceutical composition according to claim
 16. 19. A method fortreating asthma in a patient comprising administering a therapeuticallyeffective amount of a pharmaceutical composition according to claim 8.20. A method for treating asthma in a patient comprising administering atherapeutically effective amount of a pharmaceutical compositionaccording to claim 16.